The present invention relates to certain certain substituted aryl and heteroaryl derivatives as shown in Formula (Ia) that are modulators of metabolism. Accordingly, compounds of the present invention are useful in the prophylaxis or treatment of metabolic disorders and complications thereof, such as, diabetes and obesity.

Full Text

SUBSTITUTED ARYL AND HETEROARYL DERTVATIVES AS MODULATORS OF
GLUCOSE METABOLISM AND THE PROPHYLAXIS AND TREATMENT OF
DISORDERS THEREOF
FIELD OF THE INVENTION
The present invention relates to certain substituted aryl and heteroaryl derivatives that
are modulators of glucose metabolism. Accordingly, compounds of the present invention are
useful in the prophylaxis or treatment of metabolic disorders and complications thereof, such
as, diabetes and obesity.
BACKGROUND OF THE INVENTION
Diabetes mellitus is a serious disease afflicting over 100 million people worldwide. In the
United States, there are more than 12 million diabetics, with 600,000 new cases diagnosed each
year.
Diabetes mellitus is a diagnostic term for a group of disorders characterized by abnormal
glucose homeostasis resulting in elevated blood sugar. There are many types of diabetes, but the
two most common are Type I (also referred to as insulin-dependent diabetes mellitus or IDDM)
and Type II (also referred to as non-insulin-dependent diabetes mellitus or NEDDM).
The etiology of the different types of diabetes is not the same; however, everyone with
diabetes has two things in common: overproduction of glucose by the liver and little or no ability
to move glucose out of the blood into the cells where' it becomes the body's primary fuel.
People who do not have diabetes rely on insulin, a hormone made in the pancreas, to
move glucose from the blood into the cells of the body. However, people who have diabetes
either don't produce insulin or can't efficiently use the insulin they produce; therefore, they can't
move glucose into their cells. Glucose accumulates in the blood creating a condition called
hyperglycemia, and over time, can cause serious health problems.
Diabetes is a syndrome with interrelated metabolic, vascular, and neuropathic
components. The metabolic syndrome, generally characterized by hyperglycemia, comprises
alterations in carbohydrate, fat and protein metabolism caused by absent or markedly reduced
insulin secretion and/or ineffective insulin action. The vascular syndrome consists of
abnormalities in the blood vessels leading to cardiovascular, retinal and renal complications.
Abnormalities in the peripheral and autonomic nervous systems are also part of the diabetic
syndrome.
People with IDDM, which accounts for about 5% to 10% of those who have diabetes,
don't produce insulin and therefore must inject insulin to keep their blood glucose levels normal.

IDDM is characterized by low or undetectable levels of endogenous insulin production caused by
destruction of the insulin-producing ? cells of the pancreas, the characteristic that most readily
distinguishes IDDM from NIDDM. IDDM, once termed juvenile-onset diabetes, strikes young
and older adults alike,.
Approximately 90 to 95% of people with diabetes have Type II (or NIDDM). NIDDM
subjects produce insulin, but the cells in thek bodies are insulin resistant: the cells don't respond
properly to the hormone, so glucose accumulates in their blood. NIDDM is characterized by a
relative disparity between endogenous insulin production and insulin requirements, leading to
elevated blood glucose levels. In contrast to IDDM, there is always some endogenous insulin
production in NIDDM; many NIDDM patients have normal or even elevated blood insulin levels,
while other NIDDM patients have inadequate insulin production (Rotwein, R. et al. N. Engl. J.
Med. 308,65-71 (1983)). Most people diagnosed with NIDDM are age 30 or older, and half of all
new cases are age 55 and older. Compared with whites and Asians, NIDDM is more common
among Native Americans, African-Americans, Latinos, and Hispanics. In addition, the onset can
be insidious or even clinically inapparent, making diagnosis difficult.
The primary pathogenic lesion on NIDDM has remained elusive. Many have suggested
that primary insulin resistance of the peripheral tissues is the initial event Genetic
epidemiological studies have supported this view. Similarly, insulin secretion abnormalities have
been argued as the primary defect in NIDDM. It is likely that both phenomena are important
contributors to the disease process (Rimoin, D. L., et. al. Emery and Rimoin's Principles and
Practice of Medical Genetics 3rd Ed. 1:1401-1402 (1996)).
Many people with NIDDM have sedentery lifestyles and are obese; they weigh
approximately 20% more than the recommended weight for their height and build. Furthermore,
obesity is characterized by hyperinsulinemia and insulin resistance, a feature shared with
NIDDM, hypertension and atherosclerosis.
Obesity and diabetes are among the most common human health problems in
industrialized societies. In industrialized countries a third of the population is at least 20%
overweight. In the United States, the percentage of obese people has increased from 25% at the
end of the 1970s, to 33% at the beginning the 1990s. Obesity is one of me most important risk
factors for NIDDM. Definitions of obesity differ, but in general, a subject weighing at least 20%
more than the recommended weight for his/her height and build is considered obese. The risk of
developing NIDDM is tripled in subjects 30% overweight, and three-quarters with NIDDM are
overweight
Obesity, which is the result of an imbalance between caloric intake and energy
expenditure, is highly correlated with insulin resistance and diabetes in experimental animals and

human. However, the molecular mechanisms that are inv olved in obesity-diabetes syndromes are
not clear. During early development of obesity, increase insulin secretion balances insulin
resistance and protects patients from hyperglycemia (Le Stunff, et al. Diabetes 43, 696-702
(1989)). However, after several decades, ? cell function deteriorates and non-insulin-dependent
diabetes develops in about 20% of the obese population (Pederson, P. Diab. Metab. Rev. 5,505-
509 (1989)) and (Brancati, F. L., et al., Arch. Intern. Med. 159,957-963 (1999)). Given its high
prevalence in modem societies, obesity has thus become the leading risk factor for NIDDM (Hill,
J. O., et al., Science 280,1371-1374 (1998)). However, the factors which predispose a fraction of
patients to alteration of insulin secretion in response to fat accumulation remain unknown.
.Whether someone is classified as overweight or obese is generally determined on the
basis of their body mass index (BMI) which is calculated by dividing body weight (kg) by
height squared (m2). Thus, the units of BMI are kg/m2 and it is possible to calculate the BMI
range associated with minimum mortality in each decade of life. Overweight.is defined as a
BMI in the range 25-30 kg/m2, and obesity as a BMI greater than 30 kg/m2 (see TABLE
below). There are problems with this definition in that it does not take into account the
proportion of body mass that is muscle in relation to fat (adipose tissue). To account for this,
obesity can also be defined on the basis of body fat content: greater than 25% and 30% in
males and females, respectively.

As the BMI increases there is an increased risk of death from a variety of causes that
is independent of other risk factors. The most common diseases with obesity are
cardiovascular disease (particularly hypertension), diabetes (obesity aggravates the
development of diabetes), gall bladder disease (particularly cancer) and diseases of

reproduction. Research has shown that even a modest reduction in body weight can
correspond to a significant reduction in the risk of developing coronary heart disease.
Compounds marketed as anti-obesity agents include Orlistat (XENICAL™) and
Sibutramine. Orlistat (a lipase inhibitor) inhibits fat absorption directly and tends to produce a
high incidence of unpleasant (though relatively harmless) side-effects such as diarrhea.
Sibutramine (a mixed 5-HT/noradrenaline reuptake inhibitor) can increase blood pressure and
heart rate in some patients. The serotonin releaser/reuptake inhibitors fenfluramine
(Pondimin™) and dexfenfluramine (Redux™) have been reported to decrease food intake and
body weight over a prolonged period (greater than-6 months). However, both products were
withdrawn after reports of preliminary evidence of heart valve abnormalities associated with
their use. Accordingly, there is a need for the development of a safer anti-obesity agent.
Obesity considerably increases the risk of developing cardiovascular diseases as well.
Coronary insufficiency, atheromatous disease, and cardiac insufficiency are at the forefront of the
cardiovascular complication induced by obesity. It is estimated that if the entire population had an
ideal weight, the risk of coronary insufficiency would decrease by 25% and the risk of cardiac
insufficiency and of cerebral vascular accidents by 35%. The incidence of coronary diseases is
doubled in subjects less than 50 years of age who are 30% overweight The diabetes patient faces
a 30% reduced lifespan. After age 45, people with diabetes are about three times more likely than
people without diabetes to have significant heart disease and up to five times more likely to have
a stroke. These findings emphasize the inter-relations between risks factors for NIDDM and
coronary heart disease and the potential value of an integrated approach to the prevention of these
conditions based on the prevention of these conditions based on the prevention of obesity
(Perry, 1.J, et al., BMJ 10,560-564 (1995)).
Diabetes has also been implicated in the development of kidney disease, eye diseases
and nervous-system problems. Kidney disease, also called nephropathy, occurs when the
kidney's "filter mechanism" is damaged and protein leaks into urine in excessive amounts and
eventually the kidney fails. Diabetes is also a leading cause of damage to the retina at the back of
the eye and increases risk of cataracts and glaucoma. Finally, diabetes is associated with nerve
damage, especially in the legs and feet, which interferes with the ability to sense pain and
contributes to serious infections. Taken together, diabetes complications are one of the nation's
leading causes of death.
SUMMARY OF THE INVENTION
The present invention is drawn to compounds, which bind to and modulate the
activity of a GPCR referred to herein as RUP3, and uses thereof. The term RUP3, as used

herein, includes the human sequences found in GeneBank accession number XM 066873,
naturally-occurring allelic variants, mammalian orthologs, and recombinant mutants thereof. A
preferred human RUP3 for use in screening and testing of the compounds of the invention is
provided in the nucleotide sequence of Seq. ID.No:1 and the corresponding amino acid
sequence in Seq. ID.No:2.
One aspect of the present invention encompasses certain substituted aryl and
heteroaryl derivatives as shown in Formula (la):

two adjacent R10R11 groups form a 5,6 or 7 membered cycloalkyl, cycloalkenyl or
heterocyclic group with Ar1, wherein the 5, 6 or 7 membered group is optionally
substituted with halogen; or
a pharmaceutically acceptable salt, hydrate or solvate thereof.
One aspect of the present invention encompasses N-oxides of substituted aryl and
heteroaryl derivatives of Formula (Ia).
Some embodiments of the present invention include a pharmaceutical composition
comprising at least one compound of the present invention in combination with a
pharmaceutically acceptable carrier.
Some embodiments of the present invention include methods for prophylaxis or
treatment of a metabolic disorder and/or complications thereof comprising administering to an
individual in need of such prophylaxis or treatment a therapeutically effective amount of a
compound of the present invention or a pharmaceutical composition thereof.
Some embodiments of the present invention include methods for controlling or
decreasing weight gain comprising administering to an individual in need of such controlling or
decreaseing weight gain a therapeutically effective amount of a compound of the present
invention or pharmaceutical composition thereof.
Some embodiments of the present invention include methods of modulating a RUP3
receptor comprising contacting the receptor with an effective amount of a compound of the
present invention.
Some embodiments of the present invention include methods of modulating a RUP3
receptor in an individual comprising contacting the receptor with an effective amount of a
compound of the present invention.
In some embodiments the compound is an agonist.
In some embodiments the compound is an inverse agonist.
Some embodiments of the present invention include methods of modulating a RUP3
receptor in an individual comprising contacting the receptor with a compound of the present
invention wherein the modulation of the RUP3 receptor is prophylaxis or treatment of a
metabolic disorder and/or complications thereof.
Some embodiments of the present invention include methods of modulating a RUP3
receptor in an individual comprising contacting the receptor with a compound of the present
invention wherein the modulation of the RUP3 receptor controls or reduces weight gain of the
individual.

Some embodiments of the present invention include the uses of a compound of the
present invention for production of a medicament for use in prophylaxis or treatment of a
metabolic disorder.
Some embodiments, of the present invention include the uses of a compound of the
present invention for production of a medicament for use in controlling or decreasing weight
gain in an individual.
Some embodiments of the present invention include compounds, as described herein, or
a pharmaceutical composition thereof for use in a method of treatment of the human or animal
body by therapy.
Some embodiments of the present invention include compounds, as described herein,
or a pharmaceutical composition thereof for use in a method of prophylaxis or treatment of a
metabolic disorder of the human or animal body by therapy.
Some embodiments of the present invention include methods of producing a
pharmaceutical composition comprising admixing at least one compound of the present
invention and a pharmaceutically acceptable carrier.
In some embodiments the metabolic disorder or complications thereof is type I, type II
diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia,
hypertriglyceridemia, hypercholesterolemia, dyslipidemia or syndrome X. In some
embodiments the metabolic disorder is type II diabetes. In some embodiments the metabolic
disorder is hyperglycemia. In some embodiments the metabolic disorder is hyperlipidemia In
some embodiments the metabolic disorder is hypertriglyceridemia. In some embodiments the
metabolic disorder is type I diabetes. In some embodiments the metabolic disorder is
dyslipidemia. In some embodiments the metabolic disorder is syndrome X.
In some embodiments the individual is a mammal.
In some embodiments the mammal is a human,
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1A shows RT-PCR analysis of RUP3 expression in human tissues. A total of
twenty-two (22) human tissues were analyzed.
Figure 1B shows the cDNA Dot-Blot analysis of RUP 3 expression in human tissues.
Figure 1C shows analysis of RUP3 by RT-PCR with isolated huyman pancreatic
islets of Langerhans.
Figure 1D shows analysis of RUP3 expression with cDNAs of rat origin by RT-PCR.
Figure 2A shows a polyclonal anti-RUP3 antibody prepared in Rabbits.

Figure 2B shows the expression of RUP3 in insulin-producing p cells of pancreatic
islets.
Figure 3 shows functional activities of RUP3 In vitro.
Figure 4 shows a RUP3 RNA blot.
Figure 5 shows a representative scheme for the syntheses of compounds of the
present invention.
DEFINITIONS
The scientific literature that has evolved around receptors has adopted a number of terms
to refer to ligands having various effects on receptors. For clarity and consistency, the following
definitions will be used throughout this patent document
AGONISTS shall mean moieties that activate the intracellular response when they bind
to the receptor, or enhance GTP binding to membranes.
AMINO ACID ABBREVIATIONS used herein are set out in Table 1:

CHEMICAL GROUP, MOIETY OR RADICAL:
The term "C1-5 acyl" denotes an alkyl radical attached to a carbonyl wherein
the definition of alkyl has the same definition as described herein; some examples
include formyl, acetyl, propionyl, butanoyl, iso-butanoyl, pentanoyl, hexanoyl,
heptanoyl, and the like.
The term "C1-5 acyloxy" denotes an acyl radical attached to an oxygen atom
wherein acyl has the same definition has described herein; some examples include
acetyloxy, propionyloxy, butanoyloxy, iso-butanoyloxy and the like.
The term "C2-6 alkenyl" denotes a radical containing 2 to 6 carbons wherein at
least one carbon-carbon double bond is present, some embodiments are 2 to 4
carbons, some embodiments are 2 to 3 carbons, and some embodiments have 2
carbons. Both E and Z isomers are embraced by the term "alkenyl." Furthermore,
the term "alkenyl" includes di- and tri-alkenyls. Accordingly, if more than one
double bond is present then the bonds may be all E or Z or a mixtures of E and Z.
Examples of an alkenyl include vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-
pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexanyl, 2,4-hexadienyl and
the like.
The term "C1-4 alkoxy" as used herein denotes a radical alkyl, as defined
herein, attached directly to an oxygen atom. Example include for example methoxy,
ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy, iso-butoxy and the like.
The term "alkyl" denotes a straight or branched carbon radical, in some
embodiments the term C1-8 alkyl denotes an alkyl group consisting of 1 to 8 carbons,
in some embodiments there are 1 to 6 carbons, in some embodiments mere are 1 to 3
carbons, and in some embodiments there are 1 or 2 carbons. Examples of an alkyl
include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, t-butyl, amyl, t-amyl, n-
pentyl and the like.
The term "C1-4 alkylcarboxamido" denotes a single alkyl group attached to
an amide, wherein alkyl has the same definition as found herein. The C1-5
alkylcarboxamido may be represented by the following:

Examples include N-methylcarboxamide, N-ethylcarbojcamide, N-(iso-
propyl)carboxamide and the like.
The term "C1-C3 alkylene" refers to a divalent straight carbon group, such as,
-CH2-, -CH2CH2-, -CH2CH2CH2-.
The term "C1-4 alkylsulfinyl" denotes an alkyl radical attached to a sulfoxide
radical of the formula: -S(O)- wherein the alkyl radical has the same definition as
described herein. Examples include methylsulfinyl, ethylsulfinyl and the like.
The term "C1-4 alkylsulfonamide" refers to the groups
The term "C1-4 alkylsuli'onyl" denotes an alkyl radical attached to a sulfone
radical of the formula: -S(O)2- wherein the alkyl radical has the same definition as
described herein. Examples include methylsulfonyl, ethylsulfonyl and the like.
The term "C1-4 alkylthio" denotes an alkyl radical attached to a sulfide of the
formula: -S- wherein the alkyl radical has the same definition as described herein.
Examples include methylsulfanyl (i.e., CH3S-), ethylsulfanyl, isopropylsulfanyl and
the like.
The term "C1-4 alkylthiocarboxamide" denotes a thioamide of the following
formulae:

The term "C1-4 alkylthioureyl" denotes the group of the formula: -NC(S)N-
wherein one are both of the nitrogens are substituted with the same or different alkyl
group and alkyl has the same definition as described herein. Examples of an
alkylthioureyl include, CH3NHC(O)NH-, NH2C(O)NCH3-, (CH3)2N(O)NH-,
(CH3)2N(O)NH-, (CH3)2N(O)NCH3-, CH3CH2NHC(O)NH-, CH3CH2NHC(O)NCH3-,
and the like.
The term "C1-4 alkylureyl" denotes the group of the formula: -NC(O)N-
wherein one are both of the nitrogens are substituted with the same or different alkyl
group wherein alkyl has the same definition as described herein. Examples of an
alkybreyl include, CH3NHC(O)NH-, NH2C(O)NCH3-, (CH3)2N(O)NH-,

(CH3)2N(O)NH-, (CH3)2N(O)NCH3-, CH3CFLNHC(O)NH-, CH3CH2NHC(O)NCH3-,
and the like.
The term "C2-6 alkynyl" denotes a Tadical containing 2 to 6 carbons and at least
one carbon-carbon triple bond, some embodiments are 2 to 4 carbons, some
embodiments are 2 to 3 carbons, and some embodiments have 2 carbons. Examples of
an alkynyl include ethynyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-burynyl, 3-
butynyl, l-p.entynyl,2-pentynyl, 3-penrynyl,4i)entynyl, 1-hexynyl, 2-hexynyl, 3-
hexynyl, 4-hexynyl, 5-hexynyl and the like. The term "alkynyl" includes di- and tri-
ynes.
The term "amino" denotes the group -NH2-
The term C1-4 alkylamino" denotes one alkyl radical attached to an amino radical
wherein the alkyl radical hasfhe same meaning as described, herein. Some examples
include memylarnino, ethylamino, propylamino and the like.
The term "aryl" denotes an aromatic ring radical containing 6 to 10 ring
carbons. Examples include phenyl and naphthyl.
The term "arylalkyl" defines a C1-C4 alkylene, such as -CH2-, -CH2CH2- and
the like, which is further substituted with an aryl group. Examples, of an "arylalkyl"
include benzyl, pheneithylene and the like.
The term "arylcarboxamido" denotes a single aryl group attached to the
amine of an amide, wherein aryl has the same definition as found herein. The

example is N-phenylcarboxarnide.
The term "arylureyl" denotes the group -NC(O)N- where one of the
nitrogens are substituted with an aryl.
The term "benzyl" denotes the group -CH2C6H5.
The term "carbo-C1-6-alkoxy" refers to an alkyl ester of a carboxylic acid,
wherein the alkyl group is C1-6 Examples include carbomethoxy, carboethoxy,
carboisopropoxy and the like.
The term "carboxamide" refers to the group -CONH2.
The term "carboxy" or "carboxyl" denotes the group -C02H; also referred to
as a carboxylic acid.
The term "cyano" denotes the group -CN.
The term "C3-6 cycloalkenyl" denotes a non-aromatic ring radical containing
3 to 6 ring carbons and at least one double bond; some embodiments contain 3 to 5
carbons; some embodiments contain 3 to 4 carbons. Examples include

cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentenyl, cyclohexenyl, and the like.
The term "C3-6 cycloalkyl" denotes a saturated ring radical containing 3 to 6
carbons; some embodiments contain 3 to 5 carbons; some embodiments contain 3 to 4
carbons. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopenyl,
cyclohexyl, cycloheptyl and the like.
The term "C4-8 diacylamino" denotes an amino group bonded wiih two acyl
groups defined herein wherein the acyl groups may be the same or different, such as:

Represented dialkylamino groups include diacetylamino, dipropionylamino,
acetylpropionylamino and the like.
The term "C2-6 dialkylamino" denotes an amino substituted with two of the same
or different alkyl radicals wherein alkyl radical has the same definition as described
herein. Some examples include dimethylamino, methylethylamino, diethylamino and
the like.
The term "C1-4 dialkylcarboxamido" denotes two alkyl radicals, that are the
same or different, attached to an amide group, wherein alkyl has the same definition as
described herein. A C1-4 dialkylcarboxamido may be represented by the following
groups: .
Examples of a dialkylcarboxamide include N,N-dimethylcarboxamide, N-methyl-N-
ethylcarhoxamide and the like.
The term "C2-6 dialkylsulfonamide" refers to one of thefollowing groups
shown below:

The term "C1-4 dialkylthiocarboxamido" denotes two alkyl radicals, that are
the same or different, attached to a thioamide group, wherein alkyl has the same

definition-as described herein. A C1-4 dialky lthiocarboxamido may be represented by
the following groups:

Examples of a dialkylthiocarboxamide include N,N-dimethylthiocarboxamide, N-
methyl-N-ethylthiocarboxamide and the like.
The term "C1-4 dialkylsulfonylamino" refers to an amino group bonded with
two C1-4 alkylsulfonyl groups as defined herein.
The term "ethynylene" refers to the carbon-carbon triple bond group as
represented below:
The term "formyl" refers to the group -CHO.
The term "C1-4 haloalkoxy" denotes a haloalkyl, as defined herein, that is
directly attached to an oxygen to form a difluoromethoxy, trifluoromethoxy, 2,2,2-
trifiuoroethoxy, pentafluoroethoxy and the like.
The term "C1-4 haloalkyl" denotes an alkyl group, defined herein, wherein the
alkyl is substituted with one halogen up to fully substituted represented by the formula
CnF2n+1; when more than one halogen is present they may be the same or different and
selected from F, C1, Br or I. Examples include fluoromethyl, difluoromethyl,
trifluoromethyl, cluorodifluoromethyl, 2,2,2-trifluoroethyl, pentafiuoroethyl and the like.
The term "C1-4 haloalkylcarboxamide" denotes an alkylcarboxamide group, defined
herein, wherein the alkyl is substituted with one halogen up to fully substituted
represented by the formula CnF2n+1 and "n" is 1,2,3 or 4. When more than one
halogen is present they may be the same or different and selected from F, C1, Br or I.
Examples include 2-fluoroacetyl, 2,2-difluoroacetyl, 2,2,2-trifluoroacetyl, 2-chloro-2,2-
difluoroacetyl, 3,3,3-rrifluoropropionyl, 2,2,3,3,3-pentafluoropropionyl and the like. The
term "C1-4 haloalkylsulfinyl" denotes a haloalkyl radical attached to a sulfoxide of the
formula: -S(O)- wherein the alkyl radical has the same definition as described herein.
Examples include trifluoromethylsulfinyl, 2,2,2-trifiuoroethylsulfinyl, 2,2-
difluoroethylsulfinyl and the like.
The term "C1-4 haloalkylsulfonyl" denotes a haloalkyl attached to a sulfone of
the formula: -S(O)2- wherein haloalkyl has the same definition as described herein.

Examples include trifluoromethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, 2,2-
difluoroethylsulfonyl and Ihe like.
The term "C1-4 haloalkylthio" denotes an alkylthio radical substituted with
one or more halogens. Examples include trifluoromethylthio, 1,1-difluoroethylthio,
2,2,2-trifluoroethylthio and the like.
The term "halogen" or "halo" denotes to a fluoro, chloro, bromo or iodo
group.
The term "C1-2 heteroalkylene" refers to a C1-2 alkylene bonded to a
heteroatom selected from O, S, S(O), S(O)2 and NH. Some represented examples
include the groups of the following formulae:

The term "heteroaryl" denotes an aromatic ring system that may be a single
ring, two fused rings or three fused rings containing carbons and at least one ring
heteroatom selected from O, S and N. Examples of heteroaryl groups include, but not
limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, quinoline, benzoxazole,
benzothiazole, lH-benzimidazole, isoquinoline, quinazoline, quinoxaline, pyridinone
and the like.
The term "heterocyclic" denotes a non-aromatic carbon ring (i.e., cycloalkyl
or cycloalkenyl as defined herein) wherein one, two or three ring carbons are replaced
by one, two or three heteroatoms, such as, piperidinyl, rhorpholinyl, piperzinyl,
pyrrolidinyl, and the like. Additional examples of heterocyclic groups are shown in
Tables 2B, 2C, 2D, 2E, 2F and 2G, infra.
The term "heterocycHccarboxamido" denotes a heterocyclic group with a
ring nitrogen where the ring nitrogen is bonded directly to the carbonyl forming an
amide. Examples include:
and the like.
The term "heterocyclicsulfonyl" denotes a heterocyclic group with a ring
nitrogen where the ring nitrogen is bonded directly to an SO2 group forming an
sulfonamide. Examples include:

and the like.
The term "hydroxyl" refers to ihe group -OH.
The term "hydroxylamino" refers to the group -NHOH.
The term "nitro" refers to the group -NO2.
The term "C4-7 oxo-cycloalfcyl" refers to a C4-7 cycloalkyl, as defined herein,
wherein one of the ring carbons is replaced with a carbonyl. Examples of C4-7 oxo-
cycloalkyl include but are not limited to: 2-oxo-cycloburyl, 3-oxo-cycloburyl, 3-oxo-
cyclopentyl, 4-oxo-cyclohexyl, and the like and represented the following structures
respectively:

The term "perfluo roalkyt" denotes the group of the formula -CnF2n+1; stated
differently, a perfluoroalkyl is an alkyl as defined herein herein wherein the alkyl is fully
substituted with fluorine atoms and is therefore considered a subset of haloalkyl.
Examples of perfluoroalkyls include CF3, CF2CF3, CF2CF2CF3, CF(CF3)2, CF2CF2CF2CF3,
CF2CF(CF3)2, CF(CF3)CF2CF3 and the like.
The term "phenoxy" refers to the group C6H5O-.
The term "phenyl" refers to the group C6H5-.
The term"sulfonic acid" refers to the group -SO3H.
The term "terrazolyl" refers to the five membered heteroaryl of the following
formulae:
In some embodiments, the tetrazolyl group is further substituted at either the 1 or 5
position resepectively.
The term "thiol" denotes the group -SH.
CODON shall mean a grouping of three nucleotides (or equivalents to nucleotides)
which generally comprise a nucleoside (adenosine (A), guanosine (G), cytidine (C), uridine
(U) and thymidine (T)) coupled to a phosphate group and which, when translated, encodes an
amino acid

COMPOSITION shall mean a material comprising at least two compounds or two
components; for example, and ,not limitation, a Pharmaceutical Composition is a Composition.
CONTACT or CONTACTING shall mean bringing at least two moieties together,
whether in an in vitro system or an imvivo system.
IN NEED OF PROPHYLA XIS OR TREATMENT as used herein refers to a
judgment made by a caregiver (e.g. physician, nurse, nurse practitioner, etc. in the case of
humans; veterinarian in the case of animals, including non-human mammals) that an individual
or animal requires or will benefn from prophylaxis or treatment. This judgment is made based
on a variety of factors that are in the realm of a caregiver's expertise, but diat includes the
knowledge that the individual or animal is ill, or will be ill, as the result of a disease, condition
or disorder that is treatable by the compounds of the invention. In general, "in need of
prophylaxis" refers to the judgment made by the caregiver that the individual will become ill.
In this context, the compounds of the invention are used in a protective or preventive manner.
However, "in need of treatment" refers to the judgment of the caregiver mat the individual is
already ill, therefore, the compounds of the present invention are used to alleviate, inhibit or
ameliorate the disease, condition or disorder.
INDIVIDUAL as used herein refers to any animal, including mammals, preferably
mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most
preferably humans.
INHD3IT or INHD3ITING, in relationship to the term "response" shall mean that a
response is decreased or prevented in the presence of a compound as opposed to in the absence of
the compound.
INVERSE AGONISTS shall mean moieties mat bind the endogenous form of the
receptor or to me constitutively activated form of the receptor, and which inhibit the baseline
intracellular response initiated by the active form of the receptor below the normal base level of
activity which is observed in the absence of agonists or partial agonists, or decrease GTP binding
to membranes. Preferably, the baseline intracellular response is inhibited in the presence of the

inverse agonist by at least 30%, more preferably by at least 50%, and most preferably by at least
75%, as compared with the baseline response in the absence of the inverse agonist
LIGAND shall mean an endogenous, naturally occurring molecule specific for an
endogenous, naturally occurring receptor.
As used herein, the terms MODULATE or MODULATING shall mean to refer to an
increase or decrease in the amount, quality, response or effect of a particular activity,
function or molecule.

PHARMACEUTICAL COMPOSITION shall mean a composition comprising at least
one active ingredient, whereby the composition is amenable to investigation for a specified,
efficacious outcome in a mammal (for example, and not limitation, a human). Those of ordinary
skill in the art will understand and appreciate the techniques appropriate for detennining whether
an active ingredient has a desired efficacious outcome based upon the needs of me artisan.
DETAILED DESCRIPTION
One aspect of the present invention encompasses certain substituted aryl and
heteroaryl derivatives as shown in Formula (la):

or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein A, B, D, V, W, X, Y,
Z, U, and Ar1 are as described herein, supra and infra.
One aspect of the present invention encompasses N-oxides of certain substituted aryl
and heteroaryl derivatives of Formula (la).
One aspect of the present invention encompasses certain substituted aryl and
heteroaryl derivatives as shown in Formula (la) wherein:
A and B are both ethylene optionally substituted with 1 to 4 methyl groups; U
is N or CR1; D is CR2R3; V is absent;
W is -S(O)2NR4-, -NR4-, -O- or absent; X is
CR5; Y is CR6-, Z is H or nitro;
Ar1 is aryl or heteroaryl optionally substituted with R9, R10, R11, R12 and R13; R1, R5 and
R6 are each independently selected from the group consisting of H, halogen, and
nitro;
R2 is selected from the group consisting of H, C1-5 acyl, C1-8 alkyl, and
heteroaryl; and wherein C1-8 alkyl, and heteroaryl are optionally substituted with 1 to 5
substituents selected from the group consisting of C1-4 alkoxy, C1-8 alkyl, and
halogen;

or
R2 is a group of Formula (C), wherein G is S., S(O), S(O)2; and Ar4 is phenyl or
heteroaryl optionally substituted with 1 to 5 substituents selected from the group
consisting of C1-4 alkoxy, C1-8 alkyl, cyano, C1-4 haloalkoxy, C1-4 haloalkyl, and
halogen;
R3 is H;
R4 is H or C1-8 alkyl;
R9 is selected from the group consisting of C1-5 acyl, C2-6 alkenyl, C1-4 alkoxy,
C1-8 alkyl, C1-4 alkylsulfonyl, amino, arylsulfonyl, carbo-C1-6-alkoxy, carboxamide,
caTboxy, cyano, C3-4 cycloalkyl, halogen, C1-4 haloalkoxy, C1-4 haloalkyl, heterocyclic,
heteroaryl, hydroxyl, C4-7 oxo-cycloalkyl, phenyl, and sulfonic acid, and wherein C1-5
acyl, C1-8 alkyl, arylsulfonyl, heteroaryl, and phenyl are optionally substituted with 1
to 5 substituents selected independently from the group consisting of C1-4 alkoxy, C1-8
alkyl, C1-4 alkylsulfonyl, cyano, halogen, C1-4 haloalkoxy, C1-4 haloalkyl, heteroaryl,
and hydroxyl; or
R9 is a group of Formula (D) wherein "p" and "r" are independently 0,1,2 or
3; and R18 is H, carbo-C1-6-alkoxy, carboxy, heteroaryl or phenyl, and wherein the
heteroaryl and phenyl are optionally substituted with 1 to 5 substituents selected
independently from the group consisting of C1-4 alkoxy, C1-8 alkyl, halogen, C1-4
haloalkoxy, and C1-4 haloalkyl; and
R10-R13 are independently selected form the group consisting of C1-4 alkoxy,
C1-8 alkyl, amino, cyano, halogen, C1-4 haloalkoxy, C1-4 haloalkyl, and hydroxyl; or
a pharmaceutically acceptable salt, hydrate or solvate thereof. It is appreciated that
certain features of the invention, which are, for clarity, described in the context of separate
embodiments, may also be provided in combination in a single embodiment. Conversely,
various features of the invention which are, for brevity, described in the context of a single
embodiment, may also be provided separately or in any suitable subcombination.
As used herein, "substituted" indicates that at least one hydrogen atom of the
chemical group is replaced by a non-hydrogen substituents or group. When a chemical group
herein is "substituted" it may have up to the full valance of substitution; for example, a
methyl group can be substituted by 1,2, or 3 substituents, a methylene group can be
substituted by 1 or 2 substituents, a phenyl group can be substituted by 1,2,3,4, or 5
substituents, and the like.

It is understood that certain groups used to describe compounds of the present
invention contain a prefix designating the number o 'f carbons in the particular group; for
example, C1-8 alkyl is understood to encompass a one (1) carbon alkyl (i.e., methyl) to eight (8)
carbon alkyl groups.
One aspect of the present invention encompasses certain substituted aryl and
heteroaryl derivatives as shown in Formula (Ia) wherein W is -S(O)2NR4- or -NR4-. In some
embodiments W is -S(O)2NR4- and compounds may be represented by Formula (Ib) as shown
below:
wherein each variable in Formula (Ib) has the same meaning as described herein. In some
embodiments R4 is H.
One aspect of the present invention encompasses certain substituted aryl and
heteroaryl derivatives as shown in Formula (Ia) wherein W is -NR4- and compounds may be
represented by Formula (Ic) as shown below:

wherein each variable in Formula (Ic) has the same meaning as described herein. In some
embodiments R4 is H.
One aspect of the present invention encompasses certain substituted aryl and
heteroaryl derivatives as shown in Formula (Ia) wherein W is -0-, an oxygen atom, and
compounds may be represented by Formula (Id) as shown below:

wherein each variable in Formula (Id) has the same meaning as described herein.

One aspect of the present invention encompasses certain substituted aryl and
heteroaryl derivatives as shown in Formula (Ia) wherein W is S, S(O) or S(O)2 and
compounds may be represented by Formulae (Ie), (If) and (Ig) respectively as shown below:

wherein each variable in Formula (Ie), (If) and (Ig) has the same meaning as described
herein. In some embodiments W is -S-. In some embodiments W is -S(O)-. In some
embodiments W is -S(O)2-.
One aspect of the present invention encompasses certain substituted aryl and
heteroaryl derivatives as shown in Formula (Ia) wherein W is absent In some embodiments,
compounds may be represented by Formula (Ih) as shown below:

wherein each variable in Formula (Ih) has the same meaning as described herein.
In some embodiments, V is absent. In some embodiments compounds of the present
invention are of Formula (Ih) wherein V is absent (i.e., both V and W are absent) and
accordingly these compounds may be represented by Formula (Ii) as shown below:

wherein each variable in Formula (Ii) has the same meaning as described herein.
One aspect of the present invention encompasses certain substituted aryl and
heteroaryl derivatives as shown in Formula (Ia) wherein W is absent and V is ethynylene.
Compounds may be represented by Formula (Ij) as shown below:

wherein each variable in Formula (Ij) has the same meaning as described herein.
In some embodiments V is C1-3 alkylene optionally substituted with 1 to 4
substituents selected from the group consisting of C1-3 alkyl, C1-4 alkoxy and halogen.
In some embodiments V is a methylene group (i.e., -CH2-).
In some embodiments V is an ethylene group (i.e., -CH2CH2-).
In some embodiments V is a methylene and W is an oxygen atom.
In some embodiments V is methylene and W is a NR4 group.
In some embodiments V is methylene and W is a NH group.
In some embodiments V is ethylene and W is an oxygen atom.
In some embodiments V is ethylene and W is a NR4 group.
In some embodiments V is ethylene and W is a NH group.
In some embodiments V is C1-2 heteroalkylene optionally substituted with 1 to 4
substituents selected from the group consisting of C1-3 alkyl, C1-4 alkoxy and halogen.
In some embodiments V is -OCH2CH2-.
In some embodiments V is -OCH2CH2- and W is an oxygen atom and may be
represented by the formula: -OCH2CH2O-.
In some embodiments V is -OCH2CH2- and W is a NH group and may be represented
by the formula: -OCH2CH2NH-.
In some embodiments V is absent In some embodiments V is absent and may be
represented by Formula (Ik) as shown below:

wherein each variable in Formula (Ik) has the same meaning as described herein.
In some embodiments A and B are both methylene wherein A and B are optionally
substituted with 1 to 2 methyl groups and therefore form a four-membered nitrogen
containing ring. Compounds in these embodiments may be represented by Formula (Im) as
shown below:

wherein each variable in Formula (Im) has the same me;aning as described herein. In some
embodiments D is -CHR2-.
In some embodiments A is ethylene and B is methylene wherein A is optionally
substituted with 1 to 4 methyl groups and B is optionally substituted with 1 to 2 methyl
groups. Compounds in these embodiments may be represented by Formula (In) as shown
below:
wherein each variable in Formula (In) has the same meaning as described herein. In some
embodiments D is -CHR2-. In some embodiments R2 is C1-4 alkylsulfonyl.
In some embodiments A is propylene and B is methylene wherein A is optionally
substituted with 1 to 4 methyl groups and B is optionally substituted with 1 to 2 methyl
groups. Compounds in these embodiments may be represented by Formula (Io) as shown
below:
wherein each variable in Formula (Io) has the same meaning as described herein. In some
embodiments D is -CHR2-.
In some embodiments A and B are both ethylene (i.e., -CH2CH2-) wherein A and B
are optionally substituted with 1 to 4 methyl groups. In some embodiments A and B are both
ethylene. Compounds in these embodiments may be represented by Formula (Ip) as shown
below:

wherein each variable in Formula (Ip) has the same meaning as described herein. In some
embodiments, compounds of the present invention are of Formula (Ip) wherein D is CR2R3. In
some embodiments D is -CHR2-.
In some embodiments A is propylene and B is ethylene wherein A and B are
optionally substituted with 1 to 4 methyl groups. Compounds in these embodiments may be
represented by Formula (Iq) as shown below:

wherein each variable in Formula (Iq) has the same meaning as described herein. In some
embodiments D is -CHR2-.
In some embodiments A and B are both propylene wherein A and B are optionally
substituted with 1 to 4 methyl groups. Compounds in these embodiments may be represented
by Formula (Ir) as shown below:

wherein each variable in Formula (Ir) has the same meaning as described herein. In some
embodiments D is -CHR2-.
In some embodiments D is 0, S, S(O) or S(O)2.
In some embodiments D is S, S(O) or S(O)2; and A and B are independently
optionally substituted with 1 or 2 methyl groups.
In some embodiments A and B are ethylene groups.
In some embodiments A and B are ethylene groups substituted with 2 methyl groups
and D is an oxygen atom (i.e., forming a 2,6-dimethyl-morpholin-4-yl group).

wherein each variable in Formula (Ip) has the same meaning as described herein. In some
embodiments, compounds of the present invention are of Formula (Ip) wherein D is CR2R3.
In some embodiments D is -CHR2-.
In some embodiments A is propylene and B is ethylene wherein A and B are
optionally substituted with 1 to 4 methyl groups. Compounds in these embodiments may be
represented by Formula (Iq) as shown below:

wherein each variable in Formula (Iq) has the same meaning as described herein. In some
embodiments D is -CHR2-.
In some embodiments A and B are both propylene wherein A and B are optionally
substituted with 1 to 4 methyl groups. Compounds in these embodiments may be represented
by Formula (Ir) as shown below:

wherein each variable in Formula (Ir) has the same meaning as described herein. In some
embodiments D is -CHR2-.
In some embodiments D is 0, S, S(O) or S(O)2.
In some embodiments D is S, S(O) or S(O)2; and A and B are independently
optionally substituted with 1 or 2 methyl groups.
In some embodiments A and B are ethylene groups.
In some embodiments A and B are ethylene groups substituted with 2 methyl groups
and D is an oxygen atom (i.e., forming a 2,6-dimethyl-morpholin-4-yl group).

It is understood that any one of the heterocyclic groups shown in TABLES 2B to 2E may
be bonded at any available ring carbon or ring nitrogen as allowed by the respective formula. For
example, a 2,5-dioxo-imidazolidinyl group may be bonded at the ring carbon or at either of the
two ring nitrogens to give the following formulae respectively:

In some embodiments R2 is a heterocyclic represented, for example, by the formulae in
TABLE 2C.

In some embodiments R2 is a heterocyclic represented, for example, by the formulae in
TABLE 2D.

In some embodiments R2 is a heterocyclic represented, for example, by the formulae in
TABLE 2E.

In some embodiments R2 is a heterocyclic represented, for example, by the formulae in
TABLE 2F wherein the C1-6 alkyl group on the respective ring nitrogen atoms may be the
same or different

In some embodiments R2 is a heterocyclic represented, for example, by the formulae in
TABLE 2G wherein the C1-6 alkyl group on the respective ring nitrogen atoms may be the
same or different.

In some embodiments D is CR2R3 and R2 is -Ar2-Ar3 wherein Ar2 and Ar3 are
independently aryl or heteroaryl optionally substituted with 1 to 5 substituente selected from
the group consisting of H, C1-5 acyl, C1-5 acyloxy, C1-4 alkoxy, C1-8 alkyl C1-4

wherein each variable in Formula (Is) has the same meaning as described herein.
Ia some embodiments Ar2 is a heteroaryl comprising 5-atoms in the aromatic ring and
are represented by the following formulae:

wherein the 5-membered heteroaryl is bonded at any available position of the ring, for
example, a imidazolyl ring can be bonded at one of the ring nitrogens (i.e., imidazol-1 -yl
group) or at one of the ring carbons (i.e., imidazol-2-yl, imidazol-4-yl or imiadazol-5-yl
group) and Ar3 is bonded to any remaining available ring atom.
In some embodiments Ar2 is a heteroaryl and Ar3 is phenyl.
In some embodiments the heteroaryl and phenyl are optionally substituted with 1 to 5
substituents selected from the group consisting of H, C1-4 alkoxy, C1-8 alkyl, C1-4

wherein each variable in Formula (It) has the same meaning as described herein.
In some embodiments D is CR2R3, R2 is Formula (C) and G is C=0, CR16R17or O.
In some embodiments Ar4 is phenyl optionally substituted with 1 to 5 substituents
selected from the group consisting of C1-5 acyl, C1-5 acyloxy, C1-4 alkoxy, C1-8 alkyl, C1-4

wherein each variable in Formula (Iu) has the same meaning as described herein.
In some embodiments Ar2 is a heteroaryl and Ar3 is phenyl.
In some embodiments the heteroaryl and phenyl are optionally substituted with 1 to 5
substituents selected from the group consisting of H, C1-4 alkoxy, C1-8 alkyl, C1-4
alkylcarboxamide, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, C1-4 alkylthio, C1-4-haloalkoxy, C1-4
haloalkyl, halogen, hydroxyl and nitro.
In some embodiments D is N-R2 wherein R2 is Formula (C):

In some embodiments Z is selected from the group consisting of H, formyl,
NHC(O)CH3, NHC(O)CH2CH3, NHC(O)CH(CH3)2, CH3, CH2CH3, CH(CH3)2,
CH2CH2CH2CH3, NHC(O)CF3, carboxy, CF3, CF2CF3, nitro and lff-tetrazol-5-yl
In some embodiments Z is selected from the group consisting of H, carboxy, CF3,
nitro and lH-tetrazol-5-yl.
In some embodiments Z is H.
In some embodiments Z is nitro.
In some embodiments Z is Formula (A):

In some embodiments R18 is H, C1-5 acyl or C1-8 alkyl.
In some embodiments R10-R13 are independently H, C1-5 acyl, C1-4 alkoxy, C1-8 alkyl,
C1-4 alkylcarboxamide, C1-4 alkylureyl, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-6
cycloalkyl, halogen, C1-4 haloalkoxy and C1-4 haloalkyl.
In some embodiments R9 is substituted at the para position on the phenyl and may be
represented by Formula (Iw) as shown below:

wherein each variable in Formula (Iw) has the same meaning as described herein.
In some embodiments, in addition to R9 in Formula (Iw). the phenyl ring can be
optionally substituted with R10 to R13 wherein each R10 to R13 is selected independently from the
group consisting of H, C1-5 acyl, C1-4 alkoxy, C1-8 alkyl, halogen, C1-4 haloalkoxy, C1-4
haloalkyl, C1-4 haloalkylsulfinyl, C1-4 haloalkylsulfonyl, C1-4 haloalkylthio, hydroxyl and nitro.
In some embodiments, R10 to Rl3 is selected independently from the group consisting
of H and halogen.
In some embodiments Ar1 is phenyl and two adjacent R10-R11 groups form a 5,6 or 7
membercd cycloalkyl, cycloalkenyl or heterocyclic group with the phenyl group wherein the
5,6 or 7 membered group is optionally substituted with halogsn.
In some embodiments Ar1 is phenyl and two adjacent R10-R11 groups form a 5,6 or 7
membered cycloalkyl group with the phenyl group and is of the formulae shown below:

wherein "a" is 1,2 or 3 to give a 5,6 or 7 membered cycloalkyl fused together with the
phenyl group where two of the ring carbons are shared between the cycloalkyl and phenyl
group.
In some embodiments the cycloalkyl is optionally substituted with halogen.
In some embodiments the halogen is fluorine.
In some embodiments Ar1, is phenyl and two adjacent R10-R11 groups form a 5,6 or 7
membered cycloalkenyl group with the phenyl group and is of the formulae shown in TABLE

5 and has at least one carbon-carbon ring double bond present that is not part of the phenyl
group (i.e., cycloalkenyl), for example, 1H-Indenyl and dihynlro-naphthyl.
In some embodiments the heterocyclic group is optionally substituted with halogen. In
some embodiments the halogen is fluorine.
In some embodiments Ar1 is phenyl and two adjacent R10-R11 groups form a 5,6 or 7
heterocyclic group with the phenyl group and is of the formulae in TABLE 5 wherein one or
more ring cycloalkyl carbons are replaced by a O, S, S(O), S(O)2, NH or N-allcyl group.
In some embodiments the heterocyclic group is optionally substituted with halogen. In
some embodiments the halogen is fluorine.
In some embodiments Ar1 is phenyl and two adjacent R10-R11 groups form a 5
membered heterocyclic group with the phenyl group.
In some embodiments the 5 membered heterocyclic group with the phenyl group
together form a 2,3-dihydro-benzofuran-5-yl or benzo[l,3]dioxoI-5-yl group.
In some embodiments the two adjacent groups form a 6 membered heterocyclic group
with the phenyl group. In some embodiments the 6 membered heterocyclic group with the
phenyl group together form a 2,3-dihydro-benzo[l,4]dioxin-6-yl or 2,3-dihydro-
benzo[l,4]dioxin-2-yl group.
In some embodiments the two adjacent groups form a 7 membered heterocyclic group
with the phenyl group.
In some embodiments the 7 membered heterocyclic group with the phenyl group together
form a 3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl group. In some embodiments Ar1 is
heteroaryl.
In some embodiments Ar1 is a heteroaryl selected from TABLE 2A. In some embodiments
Ar1 is a heteroaryl selected from TABLE 4. In some embodiments Ar, is heteroaryl and two
adjacent R10-R11 groups form a 5,6 or 7 membered cycloalkyl, cycloalkenyl or heterocyclic
group with the heteroaryl group wherein the 5,6 or 7 membered group is optionally
substituted with halogen.
In some embodiments the two adjacent groups form a 5 membered heterocyclic group
with the heteroaryl group. In some embodiments the two adjacent groups form a 6 membered
heterocyclic group with the heteroaryl group. In some embodiments the two adjacent groups
form a 7 membered heterocyclic group with the heteroaryl group.
In some embodiments R9 is a heterocyclic group as described herein. In some embodiments
R9 is a heterocyclic group represented by the formulae shown in Table 2B, supra.

In some embodiments R9 is a heterocyclic group represented by the formulae shown in
Table 2C, supra.
In some embodiments R9 is a heterocyclic group represented by the formulae shown in
Table 2D, supra.
In some embodiments R9 is a heterocyclic group represented by the formulae shown in
Table 2E, supra.
In some embodiments R9 is a heterocyclic group represented by the formulae shown in
Table 2F, supra.
In some embodiments R9 is a heterocyclic group represented by the formulae shown in
Table 2G, supra.
In some embodiments Ar1 is phenyl, pyridyl, or pyridinone optionally substituted
with R9 and R10.
In some embodiments R9 is selected from the group consisting of C1-5 acyl, vinyl, C1-8
alkyl, C1-4 alkylsulfonyl, amino, benzenesulfonyl, carboxamide, cyclopentyl, halogen, C1-4
haloalkyl, 2,5-dioxo-imidazolidinyl, imidazolyl, pyrrolyl, triazol-l-yl, thiadiazolyl, 1,3-dioxo-
1,3-dihydro-isoindolyl, pyrazolyl, [l,3,4]oxadiazolyl, [l,2,4]oxadiazolyl, hydroxyl, oxo-
cyclohexyl, phenyl, and sulfonic acid, and wherein C1-5 acyl, C1-8 alkyl, benzenesulfonyl, and
phenyl are optionally substituted with 1 to 5 substituents selected independently from the group
consisting of C1-4 alkoxy, C1-8 alkyl, cyano, heteroaryl, and hydroxyl.
In some embodiments R9 is selected from the group consisting of is selected from the
group consisting of acetyl, 4-hydroxy-benzenesulfonyl, 2-methoxy-ethyl, vinyl, methyl,
methylsulfonyl, ethansulfonyl, amino, 4-hydroxybenzenesulfonyl, 4-cyanophenyl, 4-
methoxyphenyl, carboxamide, cyclopentyl, fluoro, chloro, bromo, trifluoromethyl, 2,5-dioxo-
imidazolidinyl, imidazol-1-yl, pyrrolyl, triazol-l-yl, thiadiazol-4-yl, l,3-dioxo-l,3-dihydro-
isoindolyl, pyrazolyl, 5-methyl-[l,3,4]oxadiazol-2-yl, 3-methyl-[l,2,4]oxadiazol-5-yl,
hydroxyl, 4-oxo-cyclohexyl, phenyl, and sulfonic acid.
In some embodiments R9 is the group of Formula (D), wherein "p" and "r" are
independently 0,1,2 or 3; and R18 is H, carbo-C1-6-alkoxy, cafboxy, heteroaryl or phenyl, and .
wherein the heteroaryl and phenyl are optionally substituted with 1 to 5 substituents selected
independently from the group consisting of C1-4 alkoxy, C1-8 alkyl, halogen, C1-4 haloalkoxy,
and C1-4 haloalkyl.
In some embodiments R9 is 2-methoxycarbonyl-acetyl, benzoyl, 3-oxo-butyl, 2-
carboxy-ethyl, 2-carboxy-2-oxo-ethyl, CH3(CH2)2C(O), CH3(CH2)3C(O), and
CH3(CH2)4C(O).

wherein each variable in Formula (IIa) has the same meaning as described herein. In some
embodiments R5 and R6 is H.
In some embodiments U is N, X is N, and Y is CR6, compounds in this embodiment
may be represented Formula (IIb) as shown below:

wherein each variable in Formula (IIb) has the same meaning as described herein. In some
embodiments R6 is H.
In some embodiments U is N, X is CR5, and Y is N, compounds in this embodiment
may be represented Formula (IIc) as shown below:

wherein each variable in Formula (He) has the same meaning as described herein. In some
embodiments R5 is H.
In some embodiments U, X and Y are N, compounds in this embodiment may be
represented Formula (IId) as shown below:

wherein each variable in Formula (IId) has the same meaning as described herein. In
some embodiments U is CR1, X is CR5 and Y is CRs, compounds in this
embodiment may be represented Formula (He) as shown below:

wherein each variable in Formula (IIe) has the same meaning as described herein. In some
embodiments R1, R5 and R6, are H.
In some embodiments U is CR1, X is N and Y is CR6, compounds in this embodiment
may be represented Formula (IIf) as shown below:

wherein each variable in Formula (IIf) has the same meaning as described herein. In some
embodiments R1 and R6 are H.
In some embodiments U is CR1, X is CR5 and Y is N, compounds in this embodiment
may be represented Formula (IIg) as shown below:

wherein each variable in Formula (IIg) has the same meaning as described herein.
In some embodiments R1 and R5 are H.
In some embodiments U is CRt, X is N and Y is N, compounds in this embodiment
may be represented Formula (Ilh) as shown below:
wherein each variable in Formula (IIh) has the same meaning as described herein.
In some embodiments X is CR5,
In some embodiments Y is CR6.
In some embodiments R5 is H.
In some embodiments U is N.
In some embodiments U is is CR1.
In some embodiments R1 is H.
In some embodiments U is N, X and Y are both CH.
In some embodiments U is CH, X is CH or C-N02, and Y is CH.
In some embodiments, the present invention include compounds wherein A and B are
both -CH2CH2-; D is CR2R3. wherein R2 is selected from the group consisting of CO2CH2CH3,
CH2CH2CH3, pyridin-2-ylsulfanyl, CH2OCH3, and S-methyl-l,2,4-oxadiazol-5-yl; and R3 is H;
V is absent, W is -O-; Z is H or nitro; and Ari is phenyl optionally substituted by R9 and R10,
wherein R9 is acetyl, vinyl, ethansulfonyl, triazol-1-yl, 2-(3-methyl-[l,2,4]oxadiazol-5-yl)-
acetyl, 5-hydroxy-l-methyl-lH-pyrazol-3-yl, 5-trifluoromethyl-pyridin-2-yl, 5-Bromo-
pyridin-2-yl, 2-methoxycarbonyl-acetyl, benzoyl, 3-oxo-butyl, 2-carboxy-ethyl, 2-carboxy-2-
oxo-ethyl, CH3(CH2)2C(O), CH3(CH2)3C(O), and CH3(CH2)4C(O); and R10 is amino; or a
pharmaceutically acceptable salt, solvate or hydrate thereof.
In some embodiments, the present invention include compounds wherein D is CR2R3,
wherein R2 is selected from the group consisting of C(O)CH3, CO2CH2CH3l CH2CH2CH3, and
pyridin-2-ylsulfanyl; and R3 is H; V is absent, W is -0-; Z is nitro; and Ari is phenyl
optionally substituted by R9 and R10, wherein R9 is acetyl, 2-methoxy-ethyl, ethansulfonyl, 4-

hydroxy-benzenesulfonyl, 4-cyanophenyl, 4-methoxypheiiyl, carboxaniide, cyclopentyl, 2,5-
dioxo-imidazolidinyl, imidazol-1-yl,pyrrolyl, triazol-l-yl, thiadiazol-4-yl, l,3-dioxo-l,3-
dihydro-isoindolyl, 4-oxo-cyclohexyl, sulfonic acid, 2-methoxycarbonyl-acetyl, and benzoyl,
3-oxo-butyl; and R10 is amino; or a pharmaceutically acceptable salt, solvate or hydrate
thereof.
Compounds disclosed herein were named accordingly to AutoNom Version 2.2
contained within Chem Draw Ultra Version 7.0.
Some embodiments of the present invention include compounds illustrated in
TABLES A and B; these TABLES are shown below.

Some embodiments of the present invention include a pharmaceutical composition
comprising at least one compound according to any of the compound embodiments disclosed
herein and a pharmaceutically acceptable carrier.
Additionally, compounds of Formula (Ia) encompass all pharmaceutically acceptable
solvates, particularly hydrates, thereof. The present invention also encompasses diastereomers as
well as optical isomers, e.g. mixtures of enantiomers including racemic mixtures, as well as
individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry
in certain compounds of Formula (Ia). Separation of the individual isomers or selective
synthesis of the individual isomers is accomplished by application of various methods which
are well known to practitioners in the art.
The phrase "pharmaceutically acceptable" is employed herein to refer to those
compounds, materials, compositions, and/or dosage forms which are, within the scope of

sound medical judgement, suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response, or other problem or
complication, commensurate with a reasonable benefit/risk ratio.
The present invention also includes pharmaceutically acceptable salts of the
compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to
derivatives of the disclosed compounds wherein the parent compound is modified by
converting an existing acid or base moiety to its salt form. Examples of pharmaceutically
acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues
such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
The pharmaceutically acceptable salts of the present invention include the conventional non-
toxic salts or the quaternary ammonium salts of the parent compound formed, for example,
from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the
present invention can be synthesized from the parent compound which contains a basic or
acidic moiety by conventional chemical methods. Generally, such salts can be prepared by
reacting the free acid or base forms of these compounds with a stoichiometric amount of the
appropriate base or acid in water or in an organic solvent, or in a mixture of the two;
generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are
preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed.,
Mack Publishing Company, Easton, Pa., 1985, p. 1418, and the most recent edition thereof;
and Journal'ofPliarmaceutical Science, 66,2 (1977), each of which is incorporated herein by
reference in its entirety.
INDICATIONS
In addition to the foregoing beneficial uses for compounds of the present invention
disclosed herein, compounds of the invention are useful in the prophylaxis or treatment of
additional diseases. Without limitation, these include the following.
The most significant pathologies in Type II diabetes are impaired insulin signaling at
its target tissues ("insulin resistance") and failure of the insulin-producing cells of the
pancreas to secrete an appropriate degree of insulin in response to a hyperglycemic signal.
Current therapies to treat the latter include inhibitors of the p-cell ATP-sensitive potassium
channel to trigger the release of endogenous insulin stores, or administration of exogenous
insulin. Neither of these achieves accurate normalization of blood glucose levels and both
carry the risk of inducing hypoglycemia. For these reasons, mere has been intense interest in
the development of pharmaceuticals that function in a glucose-dependent action, i.e.
potentiators of glucose signaling. Physiological signaling systems which function in this

manner are well-characterized and include the gut peptides GL/Pl, GIP and PACAP. These
hormones act via their cognate G-protein coupled receptor fo stimulate the production of
cAMP in pancreatic (J-cells. The increased cAMP does not appear to result in stimulation of
insulin release during the fasting or preprandial state. However, a series of biochemical
targets of cAMP signaling, including the ATP-sensiUve potassium channel, voltage-sensitive
potassium channels and the exocytotic machinery, are modified in such a way that the insulin
secretory response to a postprandial glucose stimulus is markedly enhanced. Accordingly,
agonists of novel, similarly functioning, P-cell GPCRs, including RUP3, would also stimulate
the release of endogenous insulin and consequently promote normoglycemia in Type II
diabetes.
It is also established that increased cAMP, for example as a result of GLP1
stimulation, promotes P-cell proliferation, inhibits p-cell death and thus improves islet mass.
This positive effect on P-cell mass is expected to be beneficial in both Type II diabetes, where
insufficient insulin is produced, and Type I diabetes, where p-cells are destroyed by an
inappropriate autoimmune response.
Some p-cell GPCRs, including RUP3, are also present in the hypothalamus where
they modulate hunger, satiety, decrease food intake, controlling or decreasing weight and
energy expenditure. Hence, given their function within the hypothalamic circuitry, agonists or
inverse agonists of these receptors mitigate hunger, promote satiety and therefore modulate
weight.
It is also well-established that metabolic diseases exert a negative influence on other
physiological systems. Thus, mere is often the codevelopment of multiple disease states (e.g.
type I diabetes, type II diabetes, inadequate glucose tolerance, insulin resistance,
hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia,
obesity or cardiovascular disease in "Syndrome X") or secondary diseases which clearly
occur secondary to diabetes (e.g. kidney disease, peripheral neuropathy). Thus, it is expected
that effective treatment of the diabetic condition will in turn be of benefit fo such
interconnected disease states.
Some embodiments of the present invention include a method for prophylaxis or
treatment of a metabolic disorder or complications thereof comprising administering to an
individual in need of such prophylaxis or treatment a therapeutically effective amount of a
compound of the present invention or a pharmaceutical composition thereof.
Some embodiments of the present invention include a method of decreasing food
intake comprising administering to an individual in need of decreasing food intake a

therapeutically effective amount of a compound of the present invention or pharmaceutical
composition thereof.
Some embodiments of the present invention include a method of inducing satiety
comprising administering to an individual in need of inducing satiety a therapeutically
effective amount of a compound of the present invention or pharmaceutical composition
thereof. In some embodiments the individual is a mammal. In some embodiments the
mammal is a human.
Some embodiments of the present invention include a method of controlling or
decreasing weight gain comprising administering to an individual in need of such controlling
or decreasing weight gain a therapeutically effective amount of a compound of the present
invention or pharmaceutical composition thereof.
Some embodiments of the present invention include a method of modulating a RUP3
receptor in an individual comprising contacting the receptor with a compound of the present
invention. In some embodiments the compound is an agonist m some embodiments the
compound is an inverse agonist
Some embodiments of the present invention include a method of modulating a RUP3
receptor in an individual comprising contacting the receptor with a compound of the present
invention wherein the modulation of the RUP3 receptor is prophylaxis or treatment of a
metabolic disorder and complications thereof.
Some embodiments of the present invention include a method of modulating a RUP3 receptor
in an individual comprising contacting the receptor with a compound of the present invention
wherein the modulation of the RUP3 receptor reduces food intake of the individual. Some
embodiments of the present invention include a method of modulating a RUP3 receptor in an
individual comprising contacting the receptor with a compound of the present invention
wherein the modulation of the RUP3 receptor induces satiety in the individual.
Some embodiments of the present invention include a method of modulating a RUP3
receptor in an individual comprising contacting the receptor with a compound of the present
invention wherein the modulation of the RUP3 receptor controls or reduces weight gain of the
individual.
Some embodiments of the present invention include the use of a compound of the
present invention for production of a medicament for use in prophylaxis or treatment of a
metabolic disorder.
Some embodiments of the present invention include the use of a compound of the
present invention for production of a medicament for use in decreasing food intake of an
individual.

Some embodiments of the present invention include the use of a compound of the
i
present invention for production of a medicament for use of inducing satiety in an individual.
Some embodiments of the present invention include the use of a compound of the
present invention for production of a medicament for use in controlling or decreasing weight
gain in an individual.
In some embodiments the metabolic disorder is type I, type II diabetes, inadequate
glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia,
hypercholesterolemia, dyslipidemia or syndrome X.
In some embodiments of the present invention the metabolic disorder is type II
diabetes.
In some embodiments of the present invention the metabolic disorder is
hyperglycemia.
In some embodiments of the present invention the metabolic disorder is
hyperlipidemia.
In some embodiments of the present invention the metabolic disorder is
hypertriglyceridemia.
In some embodiments of the present invention the metabolic disorder is type I
diabetes.
In some embodiments of the present invention the metabolic disorder is dyslipidemia. In
some embodiments of the present invention the metabolic disorder is syndrome X. In some
embodiments of the present invention the individual is a mammal. In some embodiments of
the present invention the mammal is a human. In some embodiments of the present invention
the human has a body mass index of about 18.5 to about 45.
In some embodiments of the present invention the human has a body mass index of
about 25 to about 45.
In some embodiments of the present invention the human has a body mass index of .
about 30 to about 45.
In some embodiments of the present invention the human has a body mass index of
about 35 to about 45.
Compounds of the present invention are identified as an agonist or an inverse agonist
using methods known to those skilled in art, such as an assay as described in Example 1.
Pharmaceutical compositions

Some embodiments of the present invention include a method of producing a
pharmaceutical composition comprising admixing at least one compound according to any of
the compound embodiments disclosed herein and a pharmaceutically acceptable carrier.
. A compound of the present invention can be formulated into pharmaceutical
compositions using techniques well known to those in the art. Suitable pharmaceutically-
acceptable carriers, outside those mentioned herein, are available to those in the art; for
example, see Remington's Pharmaceutical Sciences, 16th Edition, 1980, Mack Publishing Co.,
(Oslo et al., eds.) and the most recent edition tiiereof.
While it is possible that, for use in the prophylaxis or treatment, a compound of the
invention may in an alternative use be administered as a raw or pure chemical, it is preferable
however to present the compound or active ingredient as a pharmaceutical formulation or
composition further comprising a pharmaceutically acceptable carrier.
The invention thus further provides pharmaceutical formulations comprising a
compound of the invention or a pharmaceutically acceptable salt or derivative thereof together
with one or more pharmaceutically acceptable carriers therefor and/or prophylactic
ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the
other ingredients of the formulation and not overly deleterious to the recipient thereof.
Pharmaceutical formulations include those suitable for oral, rectal, nasal, topical
(including buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub-
cutaneous and intravenous) administration or in a form suitable for administration by
inhalation or insufflation.
The compounds of the invention, together with a conventional adjuvant, carrier, or
diluent, may thus be placed into the form of pharmaceutical formulations and unit dosages
thereof, and in such form may be employed as solids, such as tablets or filled capsules, or
liquids such as solutions, suspensions, emulsions, elixirs, gels or capsules filled with the same,
all for oral use, in the form of suppositories for rectal administration; or in the form of sterile
injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical
compositions and unit dosage forms thereof may comprise conventional ingredients in
conventional proportions, with or without additional active compounds or principles, and such
unit dosage forms may contain any suitable effective amount of the active ingredient
commensurate with the intended daily dosage range to be employed.
For oral administration, the pharmaceutical composition may be in the form of, for
example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably
made in the form of a dosage unit containing a particular amount of the active ingredient.
Examples of such dosage units are capsules, tablets, powders, granules or a

suspension, with con yentional additives such as lactose, mannitol, corn starch or potato starch;
with binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins;
with disintegrators such as corn starch, potato starch or sodium carboxymethyl-cellulose; and
with lubricant such as talc or magnesium stearate. The active ingredient may also be
administered by injection as a composition wherein, for example, saline, dextrose or water may
be used as a suitable pharmaceutically acceptable carrier.
The dose when using the compounds of Formula (Ia) can vary within wide limits, and
as is customary and is known to the physician, it is to be tailored to the individual conditions irt
each individual case. It depends, for example, on the nature and severity of the illness to be treated,
on the condition of the patient, on the compound employed or on whether an acute or chronic
disease state is treated or prophylaxis is conducted or on whether further active compounds are
administered in addition to the compounds of the Formula (Ia). Representative doses of the
present invention include, about 0.01 mg to about 1000 mg, about 0.01 to about 750 mg, about
0.01 to about 500 mg, 0.01 to about 250 mg, 0.01 mg to about 200 mg, about 0.01 mg to 150
mg, about 0.01 mg to about 100 mg, and about 0.01 mg to about 75 mg. Multiple doses may be
administered during the day, especially when relatively large amounts are deemed to be
needed, for example 2,3 or 4, doses. If appropriate, depending on individual behavior and as
appropriate from the patients physician or care-giver it may be necessary to deviate upward or
downward from the daily dose.
The amount of active ingredient, or an active salt or derivative thereof, required for
use in treatment will vary not only with the particular salt selected but also with the route of
administration, the nature of the condition being treated and the age and condition of the
patient and will ultimately be at the discretion of the attendant physician or clinician. In
general, one skilled in the art understands how to extrapolate in vivo data obtained in a model
system, typically an animal model, to another, such as a human. Typically, animal models
include, but are not limited to, the rodents diabetes models as described in Example 6, infra
(other animal models have been reported by Reed and Scribner in Diabetes, Obesity and
Metabolism, 1,1999,75-86) or the inhibition of food intake model as described in Example 7,
infra. In some circumstances, these extrapolations may merely be based on the weight of the
animal model in comparison to another, such as a mammal, preferably a human, however,
more often, these extrapolations are not simply based on weights, but rather incorporate a
variety of factors. Representative factors include the type, age, weight, sex, diet and medical
condition of the patient, the severity of the disease, the route of administration,
pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology
profiles of the particular compound employed, whether a drug delivery system is utilized, on

whether an acute or chronic disease state is being treated or prophylaxis is conducted or on
whether further active compounds are administered in addition to the compounds of the
Formula (Ia) and as part of a drug combination. The dosage regimen for treating a disease
condition with the compounds and/or compositions of this invention is selected in accordance
with a variety factors as cited above. Thus, the actual dosage regimen employed may vary
widely and therefore may deviate from a preferred dosage regimen and one skilled in the art
will recognize that dosage and dosage regimen outside these typical ranges can be tested and,
where appropriate, may be used in the methods of this invention.
The desired dose may conveniently be presented in a single dose or as divided doses
administered at appropriate intervals, for example, as two, three, four or more sub-doses per
day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced
administrations. The daily dose can be divided, especially when relatively large amounts are
administered as deemed appropriate, into several, for example 2,3 or 4, part administrations.
If appropriate, depending on individual behavior, it may be necessary to deviate upward or
downward from the daily dose indicated.
The compounds of the present invention can be administrated in a wide variety of oral
and parenteral dosage forms. It will be obvious to those skilled in the art that the following
dosage forms may comprise, as the active component, either a compound of the invention or a
pharmaceutically acceptable salt of a compound of the invention.
For preparing pharmaceutical compositions from the compounds of the present
invention, the selection of a suitable pharmaceutically acceptable carrier can be either solid,
liquid or a mixture of both. Solid form preparations include powders, tablets, pills, capsules,
cachets, suppositories, and dispersible granules. A solid carrier can be one or more
substances which may also act as diluents, flavouring agents, solubilizers, lubricants,
suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating
material.
In powders, the carrier is a finely divided solid which is in a mixture with the finely
divided active component.
In tablets, the active component is mixed with the carrier having the necessary
binding capacity in suitable proportions and compacted to the desire shape and size.
The powders and tablets may contain varying percentage amounts of the active
compound. A representative amount in a powder or tablet may contain from 0.5 to about 90
percent of the active compound; however, an artisan would know when amounts outside of
this range are necessary. Suitable carriers for powders and tablets are magnesium carbonate,
magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth,

methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the
like. The term "preparation" is intended to include the formulation of the active compound
with encapsulating material as carrier providing a capsuie in which the active component, with
or without carriers, is surrounded by a carrier, which is thus in association with it. Similarly,
cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can
be used as solid forms suitable for oral administration.
For preparing suppositories, a low melting wax, such as an admixture of fatty acid
glycerides or cocoa butter, is first melted and the active component is dispersed
homogeneously therein, as by stirring. The molten homogenous mixture is then poured into
convenient sized molds, allowed to cool, and thereby to solidify.
Formulations suitable for vaginal administration may be presented as pessaries,
tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient
such carriers as are known in the art to be appropriate.
Liquid form preparations include solutions, suspensions, and emulsions, for example,
water or water-propylene glycol solutions. For example, parenteral injection liquid
preparations can be formulated as solutions in aqueous polyethylene glycol solution.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may
be formulated according to the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a sterile injectable solution
or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed
are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed
oils are conventionally employed as a solvent or suspending medium. For this purpose any
bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty
acids such as oleic acid find use in the preparation of injectables.
The compounds according to the present invention may thus be formulated for
parenteral administration (e.g. by injection, for example bolus injection or continuous
infusion) and maybe presented in unit dose form in ampoules, pre-filled syringes, small
volume infusion or in multi-dose containers with ah added preservative. The pharmaceutical
compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous
vehicles, and may contain formulatory agents such as suspending, stabilizing and/or
dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by
aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a
suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolving the active
component in water and adding suitable .olorants, flavours, stabilizing and thickening agents, as
desired.
Aqueous suspensions suitably for oral use can be made by dispersing the finely divided
active component in water with viscous material, such as natural or synthetic gums, resins,
methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
Also included are solid form preparations which are intended to be converted, shortly
before use, to liquid form preparations for oral administration. Such liquid forms include
solutions, suspensions, and emulsions. These preparations may contain, in addition to the
active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners,
dispersants, thickeners, solubilizing agents, and the like.
For topical administration to the epidermis the compounds according to the invention
may be formulated as ointments, creams or lotions, or as a transdermal patch.
Ointments and creams may, for example, be formulated with an aqueous or oily base
with the addition of suitable thickening and/or gelling agents. Lotions maybe formulated with
an aqueous or oily base and will in general also contain one or more emulsifying agents,
stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
Formulations suitable for topical administration in the mouth include lozenges
comprising active agent in a flavored base, usually sucrose and acacia or tragacanth; pastilles
comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and
acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Solutions or suspensions are applied directly to the nasal cavity by conventional
means, for example with a dropper, pipette or spray. The formulations may be provided in
single or multi-dose form. In the latter case of a dropper or pipette, this may be achieved by
the patient administering an appropriate, predetermined volume of the solution or suspension.
In the case of a spray, this may be achieved for example by means of a metering atomizing
spray pump.
Administration to the respiratory tract may also be achieved by means of an aerosol
formulation in which the active ingredient is provided in a pressurized pack with a suitable
propellant If the compounds of the Formula (Ia) or pharmaceutical compositions comprising
them are administered as aerosols, for example as nasal aerosols or by inhalation, this can be
carried out, for example, using a spray, a nebulizer, a pump nebulizer, an inhalation apparatus,
a metered inhaler or a dry powder inhaler. Pharmaceutical forms for administration of the
compounds of the Formula (Ia) as an aerosol can be prepared by processes well-known to the

person skilled in the art. For their preparation, for example, solutions or dispersions of the
compounds of the Formula (Ia) in water, water/alcohol mixtures or suitable saline solutions
can be employed using customary additives, for example benzyl alcohol or other suitable
preservatives, absorption enhancers for increasing the bioavailability, solubilizers, dispersants
and others, and, if appropriate, customary propellants, for example include carbon dioxide,
CFC's, such as, dichlorodifluoromethane, trichlorofluoromethane, or
dichlorotetrafluoroethane; and the like. The aerosol may conveniently also contain a
surfactant such as lecithin. The dose of drug may be controlled by provision of a metered
valve.
In formulations intended for administration to the respiratory tract, including
intranasal formulations, the compound will generally have a small particle size for example of
the order of 10 microns or less. Such a particle size may be obtained by means known in the
art, for example by micronization. When desired, formulations adapted to give sustained
release of the active ingredient may be employed.
Alternatively the active ingredients may be provided in the form of a dry powder, for
example, a powder mix of the compound in a suitable powder base such as lactose, starch,
starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
Conveniently the powder carrier will form a gel in the nasal cavity. The powder composition
maybe presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or
blister packs from which the powder may be administered by means of an inhaler.
The pharmaceutical preparations are preferably in unit dosage forms. In such form,
the preparation is subdivided into unit doses containing appropriate quantities of the active
component The unit dosage form can be a packaged preparation, the package containing
discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or
ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it
can be the appropriate number of any of these in packaged form.
Tablets or capsules for oral administration and liquids for intravenous administration
are preferred compositions.
The term "prodrug" refers to compounds that are rapidly transformed in vivo to yield
the parent compound of the above formulae, for example, by hydrolysis in blood. A thorough
discussion is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems,"
Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed.
Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, botii of
which are hereby incorporated by reference.

Combination Therapy/Prophylaxis
While the compounds of the invention can be administered as the sole active
pharmaceutical agent as described herein above, they can also be used in combination with
one or more agents belonging to the class of drugs known as a-glucosidase inhibitors, aldose
reductase inhibitors, biguanides, HMG-CoA reductase inhibitors, squalene synthesis
inhibitors, fibrate compounds, LDL catabolism enhancers and angiotensin converting enzyme
(ACE) inhibitors.
?-Glucosidase inhibitors belong to the class of drugs which competitively inhibit
digestive enzymes such as a-amylase, maltase, a-dextrinase, sucrase, etc. in the pancreas and
or small intesting. The reversible inhibition by a-glucosidase inhibitors retard, diminish or
otherwise reduce blood glucose levels by delaying the digestion of starch and sugars. Some
representative examples of ?-glucosidase inhibitors include acarbose, N-(l,3-dihydroxy-2-
propyl)valiolamine (generic name; voglibose), miglitol, and ?-glucosidase inhibitors known
in the art •
The class of aldose reductase inhibitors are drugs which inhibit the first-stage rate-
limiting en2yme in the polyol pathway that prevent or arrest diabetic complications. In the
hyperglycemic state of diabetes, the utilization of glucose in the polyol pathway is increased
and the excess sorbitol accumulated intracellularly as a consequence acts as a tissue toxin and
hence evokes the onset of complications such as diabetic neuropathy, retinopathy, and
nephropathy. Examples of the aldose reductase inhibitors include tolurestat; epalrestat; 3,4-
dihydro-2,8-diisopropyl-3-thioxo-2H-l ,4-benzoxazme-4-acetic acid; 2,7-difluorospiro(9H-
fluorene-9,4'-imidazolidine)-2',5,-dione (generic name: imirestat); 3-[(4-bromo-2-
fluropaenyl)methy]-7-chloro-3,4-dihydro-2,4-dioxo-l(2H)-qumazoline acetic acid (generic
name: zenarestat); 6-fluoro-2,3 -dihydro-2',5'-dioxo-spiro[4H)-l -benzopyran-4,4'-
imidazolidine]-2-carboxamide (SNK-860); zopolrestat; sorbinil; and l-[(3-bromo-2-
benzofuranyl)sulfonyl]-2,4-imidazolidinedione (M-16209), and aldose reductase inhibitors
known in the art.
The biguanides are a class of drugs that stimulate anaerobic glycolysis, increase the
sensitivity to insulin in the peripheral tissues, inhibit glucose absorption from the intestine,
suppress of hepatic gluconeogenesis, and inhibit fatty acid oxidation. Examples of biguanides
include phenforrnin, metformin, buformin, and biguanides known in the art
Statin compounds belong to a class of drugs that lower blood cholesterol levels by
inhibiting hydroxymethylglutalyl CoA (HMG-CoA) reductase. HMG-CoA reductase is the
rate-limiting enzyme in cholesterol biosynthesis. A statin that inhibits tius reductase lowers

serum LDL concentrations by upregulating the activity of LDL receptors and responsible for
clearing LDL from the blood. Examples of the statin compounds include rosuvastatin,
pravastatin and its sodium salt, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin,
and HMG-CoA reductase inhibitors known in the art.
Squalene synthesis inhibitors belong to a class of drugs that lower blood cholesterol
levels by inhibiting synthesis of squalene. Examples of the squalene synthesis inhibitors
include (S)-a-[Bis[2,2-dimethyl-l-oxopropoxy)methoxy] phosphinyl]-3-
phenoxybenzenebutanesulfonic acid, mono potassium salt (BMS-188494) and squalene
synthesis inhibitors known in the art.
Fibrate compounds belong to a class of drugs that lower blood cholesterol levels by
inhibiting synthesis and secretion of triglycerides in the liver and activating a lipoprotein
lipase. Fibrates have been known to activate peroxisome proliferators-activated receptors and
induce lipoprotein lipase expression. Examples of fibrate compounds include bezafibrate,
beclobrate, binifibrate, ciplofibrate, clinofibrate, clofibrate, clofibric acid, etofibrate,
fenofibrate, gemfibrozil, nicofibrate, pirifibrate, ronifibrate, sirnfibrate, theofibrate, and
fibrates known in the art.
LDL (low-density lipoprotein) catabolism enhancers belong to a class of drugs that
lower blood cholesterol levels by increasing the number of LDL (low-density lipoprotein)
receptors, examples include LDL catabolism enhancers known in the art.
Angiotensin converting enzyme (ACE) inhibitors belong to the class of drugs that
partially lower blood glucose levels as well as lowering blood pressure by inhibiting
angiotensin converting enzymes. Examples of the angiotensin converting enzyme inhibitors
include captopril, enalapril, alacepril, delapril; ramipril, lisinopril, imidapril, benazepril,
ceronapril, cilazapril, enalaprilat, fosinopril, moveltopril, perindopril, quinapril, spirapril,
temocapril, trandolapril, and angiotensin converting enzyme inhibitors known in the art
Insulin secretion enhancers belong to the class of drugs having the property to
promote secretion of insulin from pancreatic ? cells. Examples of the insulin secretion
enhancers include sulfonylureas (SU). The sulfonylureas (SU) are drugs which promote
secretion of insulin from pancreatic ? cells by transmitting signals of insulin secretion via SU
receptors in the cell membranes. Examples of the sulfonylureas include tolbutamide;
chlorpropamide; tolazamide; acetohexamide; 4-chloro-N-[(l-pyrolidinylamino) carbonyl]-
benzenesulfonamide (generic name: glycopyramide) or its ammonium salt; glibenclamide
(glyburide); gliclazide; l-buiyl-3-metanilylurea; carbutamide; glibonuride; glipizide;
gliquidone; glisoxepid; glybuthiazole; glibuzole; glyhexamide; glymidine; glypinamide;
phenbutamide; tolcyclamide, glimepiride, and other insulin secretion enhancers known in the

art. Other insulin secretion enhancers include N-[[4-( i-methyIethyl)cyclohexyl)carbonyl]-D-
phenylalanine (Nateglinide); calcium (2S)-2-benzyl i-(cis-hexahydro-2-
isoindolinylcarbonyl)propionate dihydrate (Mitiglinkle, KAD-1229); and other insulin
secretion enliancers known in the art.
Thiazolidinediones belong to the class of drugs more commoningly known as TZDs.
Examples of thiazolidinediones include rosiglitazone, pioglitazone, and thiazolidinediones
known in the art.
Some embodiments of the invention include, a pharmaceutical composition
comprising a compound of Formula (Ia) or a pharmaceutically acceptable salt thereof in
combination with at least one member selected from the group consisting of an a-glucosidase
inhibitor, an aldose reductase inhibitor, abiguanide, a HMG-CoA reductase inhibitor, a
squalene synthesis inhibitor, a fibrate compound, a LDL catabolism enhancer and an
angiotensin converting enzyme inhibitor. In another embodiment, the pharmaceutical
composition is a compound of Formula (Ia) or a pharmaceutically acceptable salt thereof in
combination with a HMG-CoA reductase inhibitor. In still another embodiment, the HMG-
CoA reductase inhibitor is selected from the group consisting of pravastatin, simvastatin,
lovastatin, atorvastatin, fluvastatin and lipitor.
In accordance with the present invention, the combination can be used by mixing the
respective active components either all together or independently with a physiologically
acceptable carrier, excipient, binder, diluent, etc., as described herein above, and
administering the mixture or mixtures either orally or non-orally as a pharmaceutical
composition. When a compound or a mixture of compounds of Formula (Ia) are administered
as a combination therapy or prophylaxis with another active compound the therapeutic agents
can be formulated as a separate pharmaceutical compositions given at the same time or at
different times, or the therapeutic agents can be given as a single composition.
Other Utility
Another object of the present invention relates to radiolabelled compounds of
Formula (Ia) that would be useful not only in radio-imaging but also in assays, both in vitro
and in vivo, for localizing and quantitating RUP3 in tissue samples, including human, and for
identifying RUP3 ligands by inhibition binding of a radiolabelled compound. It is a further
object of this invention to develop novel RUP3 assays of which comprise such radiolabelled
compounds.
Suitable radionuclides mat maybe incorporated in compounds of the present
invention include but are not limited to 3H (also written as T), 11C, 14C, 18F, l25I, 82Br, 123I, I24I,

125I, 131I, 75Br, 76Br, 15O, 13N, 35S and 77Br. The radionuclide that is incorporated in the instant
radiolabelled compounds will depend on the specific application of that radiolabelled
compound. Thus, for in vitro RUP3 labeling and competition assays, compounds that
incorporate 3H, l4C, 125I, ,3II, 35S or 82Br will generally be most useful. For radio-imaging
applications 11C, 18F, l25I, l23I, 124I,1311,75Br, 76Br or 77Br will generally be most useful.
It is understood that a "radio-labelled " or "labelled compound" is a compound of
Formula (Ia) that has incorporated at least one radionuclide; in some embodiments the
radionuclide is selected from the group consisting of 3H, 14C, 1251,35S and 82Br; in some
embodiments the radionuclide 3H or 14C. Moreover, it should be understood that all of the
atoms represented in the compounds of the invention can be either the most commonly
occurring isotope of such atoms or the more scarce radio-isotope or nonradio-active isotope.
Synthetic methods for incorporating radio-isotopes into organic compounds including
those applicable to those compounds of the invention are well known in the art and include
incorporating activity levels of tritium into target molecules include: A. Catalytic Reduction
with Tritium Gas - This procedure normally yields high specific activity products and requires
halogenated or unsaturated precursors. B. Reduction with Sodium Borohydride [3H] -This
procedure is rather inexpensive and requires precursors containing reducible functional
groups such as aldehydes, ketones, lactones, esters, and the like. C. Reduction with Lithium
Aluminum Hydride [3H ] - This procedure offers products at almost theoretical specific
activities. It also requires precursors containing reducible functional groups such as
aldehydes, ketones, lactones, esters, and the like. D. Tritium Gas Exposure Labeling - This
procedure involves exposing precursors containing exchangeable protons to tritium gas in the
presence of a suitable catalyst. E. N-Methylation using Methyl Iodide [3H] - This procedure
is usually employed to prepare O-mefhyl orN-methyl (3H) products by treating appropriate
precursors with high specific activity methyl iodide (3H). This method in general allows for
high specific activity, such as about 80-87 Ci/mmol.
Synthetic methods for incorporating activity levels of ,25I into target molecules
include: A. Sandmeyer and like reactions - This procedure transforms an aryl or heteroaryl
amine into a diazonium salt, such as a tetrafluoroborate salt, and subsequently to ,25I labelled
compound using Nal25I. A represented procedure was reported by Zhu, D.-G.,and co-workers in
J. Org. Chem. 2002,67,943-948. B. Ortho l25Iodination of phenols - This procedure allows
for the incorporation of 125I at the ortho position of a phenol as reported by Collier, T. L. and
co-workers in J. Labelled Compd Radiopharm. 1999,42, S264-S266. C. Aryl and heteroaryl
bromide exchange with 125l - This method is generally a two step process. The first step is
the conversion of the aryl or heteroaryl bromide to the corresponding tri-alkyltin

intermediate using for example, a Pd catalyzed reaction [i.e. Pd(Ph3P)4] or through an aryl or
heteroaryl lithium, in the presence of a tri-alkyltinhalide or hexaalkylditin [e.g.,
(CH3)3SnSn(CH3)3]- A represented procedure was reported by Bas, M.-D. and co-workers in J.
Labelled Compd Radiopharm. 2001,44, S280-S282.
A radiolabelled RUP3 compound of Formula (I) can be used in a screening assay to
identify/evaluate compounds. In general terms, a newly synthesized or identified compound
(i.e., test compound) can be evaluated for its ability to reduce binding of the "radiolabelled
compound of Formula (Ia)" to the RUP3 receptor. Accordingly, the ability of a test
compound to compete with the "radio-labelled compound of Formula (Ia)" for the binding to
the RUP3 receptor directly correlates to its binding affinity.
The labelled compounds of the present invention bind to the RUP3 receptor. In one
embodiment the labelled compound has an IC50 less than about 500 µM, in another
embodiment the labelled compound has an IC50 less than about 100 µM, in yet another
embodiment the labelled compound has an IC50 less than about 10 µM, in yet another
embodiment the labelled compound has an IC50 less than about 1 µM, and in still yet another
embodiment the labelled inhibitor has an IC50 less than about 0.1 µM.
Other uses of the disclosed receptors and methods will become apparent to those in
the art based upon, inter alia, a review of this patent document.
The following examples are given to illustrate the invention and are not intended to be
inclusive in any manner:
EXAMPLES
The compounds of the present invention and their syntheses are further illustrated by
the following examples. The examples are provided to further define the invention without,
however, limiting the invention to the specifics of these examples.
Example 1
96- well Cyclic AMP membrane assay for RUP3
Materials:
1) Adenlyl cyclase Activation Flashplate Assay kit from Perkin Elmer - 96 wells (SMP004B)
and 125I tracer (NEX130) which comes with the kit Keep in refrigerator, in a box, and do not
expose the Flashplates to light
2) Phosphocreatine - Sigma P-7936

D, 2.5 pmole/well for row E, 1.25 pmo/'le/well for row F, 0.5 pmole/well for row G, and
0 pmole/well (buffer only) for row H.
4) Pipet 5 ul compounds from each well of a compound dilution plate, for IC50s, using the
following dilution scheme:
Well H: 400 uM compound (final concentration of compound in reaction mix
= 5/100 x 400 uM = 20 uM
Well G: 1:10 dilution of Well H (i.e. 5ul compound from well H + 45 ul
100% DMSO) (final concentration = 2 uM) Well F:
1:10 dilution of well G (final concentration = 0.2 uM) Well E: 1:10
dilution of well F (final concentration = 0.02 uM) Well D: 1:10 dilution
of well E (final concentration = 0.002 uM) Well C: 1:10 dilution of well
D (final concentration = 0.0002 uM Well B: 1:10 dilution of well C
(final concentration = 0.00002 uM) Well A: 1:10 dilution of well B (final
concentration = 0.000002 uM)
IC50S or EC50S are done in triplicate. One Flashplate can therefore be set up to handle
3 compounds, (i.e., columns 2,3, and 4 are for compound #1, columns 5,6, and 7 are
for compound #2, and columns 8,9, and 10 are for compound #3.)
5) Add 50 ul of RUP3 membranes to all wells in Columns 2 to 10. (Prior to the start of
the assay, the frozen membrane pellets for both RUP3 and CMV (cells transfected
with an expression plasmid containing no RUP3 sequences), are suspended in
binding buffer, usually 1 ml binding buffer for 1 plate of membranes. The
membranes are kept in ice all the time, and a polytron (Brinkmann polytron, model #
PT-3100) is used (setting 6-7, for 15-20 seconds) to obtain a homogeneous membrane
suspension.) Protein concentration is determined by Bradford protein assay kit using
instructions given in the kit, using the standard supplied with the kit as a reference.
The protein concentration of the membranes is adjusted with binding buffer, so that 50
ul membranes = 15 ug protein (i.e. 0.3 mg/ml protein).
6) In column 1, Wells A, B, C, and D, add 50 ul RUP3 membranes. To wells E, F, G, and
H, add 50 ul CMV membranes, (CMV membranes being of the same protein
concentration as the RUP3 membranes).

7) Incubate 1 hour at room temperature with .igitation on a rotating platform shaker.
Cover with foil while shaking.
8) After 1 hour, add (to all 96 wells), 100 ul of the 125I tracer in detection buffer supplied
with the Flashplate kit plus proclin, made up in the following manner.
Pipet per 10 ml per Flashplate: 100 ml of detection buffer + 1 ml 125I + 0.2 ml of Proclin
(the proclin helps to stop the production of cAMP). Make a smaller quantity of detection
buffer mix if you have fewer plates.
9) Shake the plates on a rotating platform shaker for 2 hours, covering the plates with
lead sheeting.
10) Seal the plates with the plastic film sealers provided with the Flashplate kit.
11) Count the plates using a TRILUX 1450 Microbeta Counter. See the door of the
counter to determine which counting protocol to use.
12) Data is analyzed on the Arena Database according to the RUP3 non-fusion, IC50 EC50
for 96-well cAMP membrane assay, and the compound numbers and the
concentrations of compounds must be entered by the user.
B. Membrane Cyclase Criteria
1) Signal to Noise:
. An acceptable signal-to-noise ratio for RUP3 can vary from 4 to 6. The raw cpms are
approximately 1800 to 2500 for RUP3 and 3500-4500 for CMV. The cpm (or
ultimately pmoles of cAMP/well) cannot be outside the standard curve, and should
not approach well A of the standard curve (50 pmole/well) and well H (no cAMP).
Generally, the pmoles of cAMP produced by RUP3 receptor are around 11 to 13
pmole/well (for 15 ug/well protein), and for CMV are between 2 to 3 pmole/well (for
15 ug protein /well).
2) Standard curve:"

The slope should be linear and the error bars fo duplicates should be very small. The
receptor and CMV controls cannot be off scale of the standard curve, as described
above. If the receptor controls are off the high end of the standard curve,i.e. 50
pmole/well or higher, one must repeat the experiment using less protein. However, such
a case has not been observed with, transiently transfected RUP3 membranes (10 ug
DNA/15 cm plate, using 60 ul Lipofectamine, and preparing membranes after 24 hour
of transfection.)
3) The IC50 or EC50 curve should be at 100% (+ or - 20%) of control RUP3 membranes at the
top, and should go down to 0 (or up to 20%) at the bottom. The standard error of the
triplicate determinations should be + or - 10%.
The compounds in the Examples, infra, were screened in the Membrane Cyclase Assay.
Representative compounds are shown in the table below:

The other compounds in the Examples were tested and they showed IC50 activities in
the membrane cyclase assay less than about 500 µM.
C. Stimulation of cAMP in HTT-T15 cells
HTT-T15 (ATCC CRL#1777) is an immortalized hamster insulin-producing cell line.
These cells express RUP3 and therefore can be used to assess the ability of RUP3 ligands to
stimulate or inhibit cAMP accumulation via its endogenously expressed receptor. In this
assay, cells are grown to 80% confluence and then distributed into a 96-well Flasbplate
(50,000 cells/ well) for detection of cAMP via a "cAMP Flashplate Assay" (NEN, Cat #
SMP004). Briefly, cells are placed into anti-cAMP antibody-coated wells that contain either
vehicle, the test ligand(s) at a concentration of interest, or 1 uM forskolin. The latter is a
direct activator of adenylyl cyclase and serves as a positive control for stimulation of cAMP in
HTT-T15 cells. All conditions are tested in triplicate. After a 1 hour incubation to allow

for stimulation of cAMP, a Detection Mix containing 125I-cAMp is added to each well and the
plate is allowed to incubate for another 1 hour. The wells are then aspirated to remove
unbound l2SI-cAMP. Bound 125I-cAMP is detected using a Wallac Microbeta Counter. The
amount of cAMP in each sample is determined by comparison to a standard curve, obtained
by placing known concentrations of cAMP in some wells on the plate.
D. Stimulation of insulin secretion in HIT-T15 cells
It is known that stimulation of cAMP in HIT-T15 cells causes an increase in insulin
secretion when the glucose concentration in the culture media is changed from 3mM to 15
mM. Thus, RTJP3 ligands can also be tested for their ability to stimulate glucose-dependent
insulin secretion (GSIS) in HIT-T15 cells. In this assay, 30,000 cells/well in a 12-well plate
are incubated in culture media containing 3 mM glucose and no serum for 2 hours. The
media is then changed; wells receive media containing either 3 mM or 15 mM glucose, and in
both cases the media contains either vehicle (DMSO) or RUP3 ligand at a concentration of
interest. Some wells receive media containing 1 uM forskolin as a positive control. All
conditions are tested in triplicate. Cells are incubated for 30 minutes, and the amount of
insulin secreted into the media is determined by ELIS A, using a kit from either Peninsula
Laboratories (Cat # ELIS-7536) or Crystal Chem Inc. (Cat # 90060).
£. Stimulation of insulin secretion in isolated rat islets
As with HIT-T15 cells, it is known that stimulation of cAMP in isolated rat islets
causes an increase in insulin secretion when the glucose concentration in the culture media is
changed from 60 mg/dl to 300 mg/dl. RUP3 is an endogenously expressed GPCR in the
insulin-producing cells of rat islets. Thus, RUP3 ligands can also be tested for their ability to
stimulate GSIS in rat islet cultures. This assay is performed as follows:
A. Select 75-150 islet equivalents (IEQ) for each assay condition using a dissecting
microscope. Incubate overnight in low-glucose culture medium. (Optional.)
B. Divide the islets evenly into triplicate samples of 25-40 islet equivalents per
sample. Transfer to 40 µm mesh sterile cell strainers in wells of a 6-well plate
with 5 ml of low (60 mg/dl) glucose Krebs-Ringers Buffer (KRB) assay
medium.

C. Incubate 30 minutes (1 hour if overnight step skipped) at 37°C and 5% CO2.
Save the supernatants if a positive control for the RIA is desired.
D. Move strainers with islets to new wells with fviul/well low glucose KRB. This is
the second pre-incubation and serves to remove residual or carryover insulin
from the culture medium. Incubate 30 minutes.
E. Move strainers to next wells (Low 1) with 4 or 5 ml low glucose KRB. Incubate
@ 37° C for 30 minutes. Collect supernatants into low-binding polypropylene
tubes pre-labelled for identification and keep cold.
F. Move strainers to high glucose wells (300mg/dl, which is equivalent to
16.7mM). Incubate and collect supernatants as before. Rinse islets in then-
strainers in low-glucose to remove residual insulin. If the rinse if to be collected
for analysis, use one rinse well for each condition (i.e. set of triplicates.)
G. Move strainers to final wells with low-glucose assay medium (Low 2). Incubate
and collect supernatants as before.
H. Keeping cold, centrifuge supernatants at 1800rpm for 5 minutes @ 4-8°C to
remove small islets/islet pieces that escape the 40mm mesh. Remove all but
lower 0.5 - 1 ml and distribute in duplicate to pre-labelled low-binding tubes.
Freeze and store at
I. Insulin determinations are done as above, or by Linco Labs as a custom service,
using their rat insulin RIA (Cat. # RI-13K).
Example 2
A. RT-PCR analysis of RUP3 expression in human tissues (Figure 1A).
RT-PCR was applied to determine the tissue distribution of RUP3. Oligonucleotides
used for PCR had the following sequences:
ZC47: 5'-CATTGCCGGCTGTGGTTAGTGTC-3' (forward primer), (SEQ ID
NO:3);
ZC48: 5'-GGCATAGATGAGTGGGTTGAGCAG-3' (reverse primer), (SEQ ID
NO:4);
and the human multiple tissue cDNA panels (MTC, Clontech) were used as templates
(1 ng cDNA per PCR amplification). Twenty-two (22) human tissues were analyzed. PCR
was performed using Platinum PCR SuperMix (Life Technologies, Inc.; manufacture

instructions were followed) in a 50 µl reaction by the following sequences: step 1, 95°C for 4
min; step 2, 95°C for 1 min; step 3, 60°C for 30 sec; step 4,72°C for 1 min; and step 5,72°C
for 7 min. Steps 2 through 4 were repeated 35 times.
The resulting PCR reactions (15 µl) were loaded on a 1.5% agarose gel to analyze the
RT-PCR products, and a specific 466 base-pair DNA fragment representing RUP3 was
specifically amplified from cDNA of pancreas origin. Low expression was also evident in
subregions of brain.
B. cDNA Dot-Blot analysis of RUP3 expression in human tissues (Figure 1B).
Results from RT-PCR analysis were further confirmed in cDNA dot-blot analysis. In
this assay, a dot-blot membrane containing cDNA from 50 human tissues (Clontech) was
hybridized with a 32P-radiolabelled DNA probe having sequences derived from human RUP3.
Hybridyzation signals were seen in pancreas and fetal liver, suggesting these tissues express
RUP3. No significant expression was detected in other tissues analyzed.
C. Analysis of RUP3 by RT-PCR with isolated human pancreatic islets of Langerhans
(Figure 1C).
Further analysis of RUP3 by RT-PCR with isolated human pancreatic islets of
Langerhans showed robust expression of RUP3 in islet cells but not in control samples.
D. Analysis of RUP3 expression with cDNAs of rat origin by RT-PCR (Figure ID).
RUP3 expression was further analyzed with cDNAs of rat origin by RT-PCR
technique. Tissue cDNAs used for this assay were obtained from Clontech except those for
hypothalamus and islets, which were prepared in house. Concentrations of each cDNA
sample were normalized via a control RT-PCR analysis of the house-keeping gene GAPDH
before assaying for RUP3 expression. Oligonucleotides used for PCR had the following
sequences:
ratRUP3 ("rRUP3") forward: 5,-CATGGGCCCTGCACCTTCTTTG-3, (SEQ ID
NO:5);
rRUP3 reverse: 5'-GCTCCGGATGGCTGATGATAGTGA-3' (SEQ ID NO: 6).
PCR was performed using Platinum PCR SuperMix (Life Technologies, Inc.; manufacture
instructions were followed) in a 5Q ul reaction by the following sequences: step 1,95°C for 4
min; step 2,95°C for 1 min; step 3,60°C for 30 sec; step 4,72°C for 1 min; and step 5,72°C
for 7 min. Steps 2 through 4 were repeated 35 times.

The resulting PCR reactions (15 µl) were loaded on a 1.5% agarose gel to analyze the
RT-PCR products, and a specific 547 base-pair DNA fragment representing rat RUP3 was
specifically amplified from cDNA of pancreas origin, revealing a similar expression profile
with human. Of particular note, robust expression was seen in isolated islets and
hypothalamus.
Example 3
RUP3 protein expression is restricted to ? cell lineage of pancreatic islets (Figure 2).
A. A polyclonal anti-RUP3 antibody was prepared in rabbits (Figure 2A).
Rabbits were immunized with an antigenic peptide with sequence.derived from rat
RUP3 ("rRUP3"). The peptide sequence was RGPERTRESAYHIVTISHPELDG (SEQ ID
NO: 7) and shared 100% identity with mouse RUP3 in the corresponding region. A cysteine
residue was incorporated at the N-terminal end of this antigenic peptide to facilitate KLH
crosslinking before injecting into rabbits. The resulting antisera ("anti-rRUP3") and the
corresponding preimmune sera ("pre-rRTJP3") were tested for immune reactivity to mouse
RUP3 in immunobloting assays (lanes 1 thought 4). In this assay, the GST-RUP3 fusion
protein was readily recognized by the anti-rRUP3 antisera (lane 4), but not by the preimmune
sera (lane 2). The immunoreactive signal could be efficiently eliminated when the
immunobloting assay was performed in the presence of excess antigenic peptide (lane 6).
B. RUP3 expression in insulin-producing ? cells of pancreatic islets (Figure 2B).
Rat pancreas was perfused with 4% paraformaldehyde (PFA) in PBS and embedded
in OCT embedding medium.-Ten micron sections were prepared, fixed on glass slides, and
immunostained with either pre-rRUP3 (Figure 2B, panel a) or with anti-rRUP3 antisera
(Figure 2B, panels c and e) followed by secondary staining with donkey anti-rabbit IgG
conjugated to the fluorochrome Cy-3. Each section was also co-immunostained with a
monoclonal anti-insulin antibody (Santa Cruz, Figure 2B, panels b and d) in primary staining
followed by a secondary staining with donkey anti-mouse IgG conjugated'with FTTC, or with a
goat anti-glucagon antibody (Santa Cruz, Figure 2B, panel f) and donkey anti-goat IgG
coupled to FITC. Immunofluorescent signals were examined under a fluorescent microscope.
RUP3 was found expressed in insulin producing cells (panels c and d), but not in glucagons
producing cells (panels e and f). These data demonstrated that RUP3 is expressed in ? cells
but not in ? cells of the rat pancreatic islets. Analogous results were obtained when mouse
pancreatic sections were investigated for RUP3 expression.

Example 4
Functional Activities of RUP3 In Vitro (FV-gure 3).
It was established thatRUP3 stimulates the production of cAMP by cotransfection of
293 cells with: (1) a CRE-Luciferase teporter, wherein the ability to stimulate the production of
firefly luciferase depends on increased cAMP in cells, and (2) an expression plasmid encoding
the human form of ROT3 (Figure 3A). Note that cells co-transfected with an expression
plasmid containing no RUP3 sequences ("CMV" in Figure 3A) produce very little luciferase
activity, whereas cells transfected with an expression plasmid encoding RUP3 (Figure 3A)
have at least a 10-fold increase in luciferase activity. This indicates that RUP3 stimulates the
production of cAMP when introduced into 293 cells. This property of RUP3 is conserved
across species, because hamster RUP3 stimulates luciferase activity when introduced into 293
cells in a manner analogous to that described for human RUP3 (Figure 3B).
It is established that, when cAMP is increased in insulin-producing cells of the
pancreas, these cells exhibit an enhanced ability to secrete insulin when glucose
concentrations rise. To test whether RUP3 might impart enhanced glucose-dependent insulin
release, retrovirus containing human RUP3 was used to generate Tu6 cells that express high
levels of RUP3. Tu6 cells produce insulin, but do not express appreciable levels of RUP3
and do not normally exhibit an increase in insulin release when increased glucose is present in
the culture media. As shown in Figure 3C, Tu6 cells transduced with a control virus that
contains no receptor are still able to produce insulin, but do not show an increase in insulin
secretion when the concentration of glucose in the culture media is shifted from 1 mM to 16
mM. By contrast, Tu6 cells transduced with RUP3-containing retrovirus display significant
glucose-dependent insulin secretion (Figure 3C).
Example 5
Functional Activities of RUP3 Agonists In Vitro.
To demonstrate that RUP3 agonists stimulate endogenously expressed RUP3 in
insulin-producing cells, two in vitro models can be used. In the first of these, RUP3 agonists
are used to stimulate HIT-T15 cells, which express RUP3 at significant levels, as indicated in
the Northern blot shown in Figure 4. Moreover, these cells are known to exhibit enhanced
glucose-dependent insulin release when intracellular cAMP concentrations are elevated. In
this example a RUP3 agonist can be evaluated for its ability to stimulate cAMP production in
HIT cells in comparison to the level seen with the adenyl cyclase activator forskolin. In this

assay Compound A30 has been shown to be a robust stimulatf.tr of cAMP in HIT-T15 cells.
Furthermore, Compound A30 has also been shown to stimulate insulin secretion in HIT cells
exposed to 15 mM glucose (at a level comparable to that seen with the adenyl cyclase
activator forskolin). This indicates that Compound A30 is a very robust potentiator of insulin
secretion in HIT-T15 cells.
Isolated rat islets are the other in vitro model used to demonstrate the efficacy of
RUP3 agonists. In this model, agents that induce cAMP are not expected to stimulate insulin
secretion when glucose concentrations are low (e.g. 60 mg/dl). However, when glucose
concentrations are increased (e.g. to 300 mg/dl), these agents are expected to enhance insulin
secretion to levels above those seen with glucose alone. In this model Compound A30 (10
µM) was shown to enhance glucose-dependent insulin release. Moreover, the level of
enhancement can be compared to that seen with 25 nM GLP-1, a gut hormone known to act
on islets in this manner.
Example 6
In vivo effects of RUP3 agonists on glucose homeostasis in mice.
A. Oral Glucose tolerance test (oGTT).
Male C57bl/6N mice at age of 8 weeks are fasted for 18 hours and randomly grouped
(n=l 1) to receive a RUP3 agonist doses, or with control extendin-4 (ex-4,1 p-g/kg), a GLP-1
peptide analog known to stimulate glucose-dependent insulin secretion. A test compound is
delivered, such as for example, orally via a gavage needle (p.o. volume at 100 µl). Control
Ex-4 is delivered intraperitoneally. Thirty minutes after administration of test compound and
control ex-4, mice are administered orally with dextrose at 5 g/kg dose. Levels of blood
glucose are determined at the indicated time points using Glucometer Elite XL (Bayer).
B. Acute response of db mice to RUP3 agonist.
Male db mice (C57BL/Ks01ahsd-Leprdb, diabetic, Harlan) at age of 10 weeks are
randomly grouped (n=6) to receive vehicle (oral gavage), test compound, (such as for
example 60 mg/kg, oral gavage), or Ex-4 (1 µg/kg, intraperitoneally). After compound
administration, food is removed and blood glucose levels are determined at selected times.
Reduction in blood glucose at each time point is expressed as percentage of original glucose
levels, averaged from six animals for each group. These animals had blood glucose levels
(fed state) of 300-400 mg/dl, significantly higher man non-diabetic wild type animals.
Treatment with Ex-4 significantly reduced glucose levels compared to vehicle control.

Example 7
Inhibition Of Food Intake In Normal Fed Male Sprague-Dawley Rats
The in vivo activity of a test compound is assayed for its ability to regulate feeding
behavior by measuring food consumption in normal fed rats during their dark cycle. Food
intake is monitored over the dark phase since animals consume most of their food intake
during the nocturnal period.
The test compound is assessed following acute administration. The study is based on a
between-subject design (n=8 per group) and the effects of various doses of the test compound
is compared to those of vehicle and a positive control. Rats [male Sprague-Dawley rats (220-
300g)] naive to drug treatment (i.e. never been exposed to drug prior to study). The anorectic
drug d-fenfluramine (or, alternatively, exendin-4) serves as a positive control.
Prior to the study, the animals are weighed and separated into treatment groups in
order to balance groups according to body weight On the test day, animals are placed into
individual cages for an hour. After this habituation period, animals are administered the test
compound at doses, such as, 6.67,20 and 60 mg/kg dissolved in 80% PEG400,10% Tween
80 and 10% EtOH. The compound is administered intraperitoneally (volume of lcc/kg) 30
min prior to the beginning of the dark phase. Animals are subsequently presented with a pre-
weighed food cup with standard laboratory chow. Food consumption is determined by
weighing the food cup at 2,4,6 and 22hr after the beginning of the dark cycle (i.e. lights off).
Care is taken to collect all spillage. The food intake of animals in the different groups is
monitored concurrently.
Food intake data is subjected to two-way repeated analysis of variance (ANOVA) with
drug treatment as a between-subject factor and time as a repeated factor. Newman-Keuls tests are
performed to assess whether differences between the vehicle mean and the drug-treated mean at
each time point were significant. All statistical analyses are performed using Sigma Stat
(version 2.0)
Example 8
CRE-Luciferase Assay in 293 Cells
293 cells were plated in 96-well tissue culture plates at a concentration of 20,000 cells
per well. The following day, the cells are transfected with a mixture of pCRE-Luc
(Stratagene, Cat # 219076), the indicated expression plasmid, and pEGFP-Nl (Clontech, Cat
# 6085-1) at a ratio of 5:1:0.25 using Lipofectamine Reagent Cuivitrogen, Cat #18324-020)

according to the manufacturer's directions. pEGFP-Nl en .odes a "green fluorescent protein"
and was used as a control to determine that most cells were successfully transfected. After 24-
48 hr, the cells were lysed in situ with 100 ul/ well recsnstituted Luclite buffer (Luclite
Reporter Gene Assay Kit, Packard, Cat. # 6016911), according to the manufacturer's
directions. After a 10 minute incubation in the dark, lunminescence was measured using a
TRILUX 1450 Microbeta Counter (Wallac).
Example 9
Generation of Tu6/ RTJP3 Stable Lines
To produce Tu6 cells that express RUP3 at high levels, a retrovirus bearing an
expression cassette for RUP3 was generated. Briefly, RUP3 coding sequence was cloned into
the retroviral vector pLNCX2 (Clontech, Cat # 6102-1). The amphotropic packaging cell line
PT-67 (Clontech, K1060-D) was then transfected with either the parental vector pLNCX2 or
pLNCX2/RUP3 using Lipofectamine and stable lines were established using guidelines
provided by the PT-67 vendor. Retrovirus-containing supernatant was obtained by collecting
media from the resultant stables according to the manufacturer's directions. Tu6 cells, in a 10
cm dish, were then infected with retrovirus by incubating in a solution of 1 ml viral
supernatant/ 9 ml culture media containing 40 ug/ml polybrene for 24 hours. The medium
was then changed to culture media containing 300 ug/ml G418. G418-resistant clones were
ultimately created by virtue of the neomycin-resistance gene cassette present in the pLNCX2
vector, thus indicating the successful integration of retrovirus into the Tu6 genome. The
expression of RUP3 in the Tu6/RUP3 G418-resistant colonies was confirmed by Northern
blot
Example 10
Insulin secretion, Tu6 Stables
To measure insulin secretion from rodent insulin-producing cell lines, cells were first
cultured overnight in serum-free, glucose-deficient media. The following morning, the cells
were then placed in the same media supplemented with either 1 mM or 16 mM glucose. After
an incubation of 4 hours, the media was collected and analyzed for insulin content using a Rat
Insulin Enzyme-Immunoassay (EIA) System (Amersham Pharmacia Biotech, Cat # RPN
2567). Typically, the assay was performed using multiple dilutions of sample media in order
to ensure that the sample measurements fell within the boundaries of the standard curve
(generated using known amounts of insulin), as recommended by the manufacturer.

Example 11 RUP3
RNA Blot
To determine the expression of RUP3 in insulin-producing or non'islet cells, the following
cell lines were obtained and cultured according to guidelines provided by American Type Culture
Collection or the indicated provider.

Total RNA was isolated from each of these cell lines using TRIZOL (Invitrogen, Cat # 15596-018),
subjected to electrophoresis through an agarose/formaldehyde gel and an RNA blot was prepared
using standard molecular biological techniques. A radiolabeled RUP3 probe, corresponding to the
full-length coding sequence of RUP3, was prepared using a Prime-It II Random Primer Labeling
Kit (Stratagene, Cat # 300385). The denatured probe, 10 ml ExpressHyb solution (Clontech, Cat #
8015-2) and the RNA blot were incubated in a hybridization oven, washed and exposed to film
using standard molecular biology practices.
Example 12
Receptor Binding Assay
In addition to the methods described herein, another means for evaluating a test
compound is by determining binding affinities to the RUP3 receptor. This type of assay generally
requires a radiolabelled ligand to the RUP3 receptor. Absent the use of known ligands for the
RUP3 receptor and radiolabels thereof, compounds of Formula (Ia) can be

labelled with a radioisotope and used in an assay for evaluating the affinity of a test
compound to the RUP3 receptor.
A radiolabelled RUP3 compound of Formula (I) can be used in a screening assay to
identify/evaluate compounds. In general terms, a newly synthesized or identified compound
(i.e., test compound) can be evaluated for its ability to reduce binding of the "radiolabelled
compound of Formula (Ia)" to the RUP3 receptor. Accordingly, the ability to compete with
the "radio-labelled compound of Formula (Ia)" or Radiolabelled RUP3 Ligand for the
binding to the RUP3 receptor directly correlates to its binding affinity of the test compound to
the RUP3 receptor.
ASSAY PROTOCOL FOR DETERMINING RECEPTOR BINDING FOR RUP3:
A. RUP3 RECEPTOR PREPARATION
293 cells (human kidney, ATCC), transiently transfected with 10 ug human RUP3
receptor and 60 ul Lipofectamine (per 15-cm dish), were grown in the dish for 24 hours (75%
confluency) with a media change and removed with 10 ml/dish of Hepes-EDTA buffer
(20mM Hepes + 10 rriM EDTA, pH 7.4). The cells were then centrifuged in a Beckman
Coulter centrifuge for 20 minutes, 17,000 rpm (JA-25.50 rotor). Subsequently, the pellet was
resuspended in 20 mM Hepes + 1 mM EDTA, pH 7.4 and homogenized with a 50- ml Dounce
homogenizer and again centrifuged. After removing the supernatant, the pellets were stored at
-80°C, until used in binding assay. When used in the assay, membranes were thawed on ice for
20 minutes and then 10 mL of incubation buffer (20 mM Hepes, 1 mM MgCI2,100 mM NaCl,
pH 7.4) added. The membranes were then vortexed to resuspend the crude membrane pellet
and homogenized with a Brinkmann PT-3100 Polytron homogenizer for 15 seconds at setting
6. The concentration of membrane protein was determined using the BRL Bradford protein
assay.
B. BINDING ASSAY
For total binding, a total volume of 50ul of appropriately diluted membranes (diluted
in assay buffer containing 50mM Tris HC1 (pH 7.4), 10mM MgCl2, and ImM EDTA; 5-50ug
protein) is added to 96-well polyproylene microtiter plates fol10wed by addition of l00ul of
assay buffer and 50ul of Radiolabelled RUP3 Ligand. For nonspecific binding, 50 ul of
assay buffer is added instead of 100ul and an additional 50ul of 10uM cold RUP3 is added
before 50ul of Radiolabelled RUP3 Ligand is added. Plates are then incubated at room -
temperature for 60-120 minutes.' The binding reaction is terminated by filtering assay plates
through a Microplate Devices GF/C Unifilter filtration plate with a Brandell 96-well plate

harvester fol10wed by washing with cold 50 mM Tris HC1, pU 7.4 containing 0.9% NaCl.
Then, the bottom of the filtration plate are sealed, 50ul of Opiiphase Supermix is added to
each well, the top of the plates are sealed, and plates are counted in a Trilux MicroBeta
scintillation counter. For compound competition studies, instead of adding 100ul of assay
buffer, 100ul of appropriately diluted test compound is added to appropriate wells fol10wed by
addition of 50ul of Radiolabelled RUP3 Ligand.
C. CALCULATIONS
The test compounds are initially assayed at 1 and 0.1 uM and then at a range of
concentrations chosen such that the middle dose would cause about 50% inhibition of a
Radio-RUP3 Ligand binding (i.e., IC50). Specific binding in the absence of test compound
(B0) is the difference of total binding (BT) minus non-specific binding (NSB) and similarly
specific binding (in the presence of test compound) (B) is the difference of displacement
binding (BD) minus non-specific binding (NSB). IC50 is determined from an inhibition
response curve, 10git-10g p10t of % B/Bo vs concentration of test compound.
Kj is calculated by the Cheng and Prustoff transformation: Ki
= IC5o/(l+[L]/KD)
where [L] is the concentration of a Radio-RUP3 Ligand used in the assay and KD is
the dissociation constant of a Radio-RUP3 Ligand determined independently under the same
binding conditions.
CHEMISTRY SYNTHESES OF
COMPOUNDS OF THE PRESENT INVENTION
EXAMPLE 13
Illustrated syntheses for compounds of Formula (Ia) are shown in Figure 5 where the
symbols have the same definitions as used throughout this disc10sure.
Chemistry:
Proton nuclear magnetic resonance ('H NMR) spectra were recorded on a Varian
Mercury Vx-400 equipped with a 4 nucleus auto switchable probe and z-gradient or a Bruker
Avance-400 equipped with a QNP (Quad Nucleus Probe) or a BBI (Broad Band Inverse) and
z-gradient Chemical shifts are given in parts per million (ppm) with the residual solvent
signal used as reference. NMR abbreviations are used as fol10ws: s = singlet, d = doublet, t =
triplet, q = quartet, m = multiple:, br = broad. Microwave irradiations were carried out using

Those skilled in the art will recognize that various modifications, additions,-
substitutions, and variations to the illustrative examples set forth herein can be made without
departing from the spirit of the invention and are. 'therefore, considered within the scope of the
invention. All documents referenced above, iacluding, but not limited to, printed publications,
and provisional and regular patent applicaticns, are incorporated herein by reference in their
entirety.

3. A compound as claimed in claim 1 or 2, wherein W is -S(O)2NR4-.
4. A compound as claimed in claim 1 or 2, wherein W is -NR4-.
5. A compound as claimed in claim 3 or 4, wherein R4 is H.
6. A compound as claimed in claim 1 or 2, wherein W is -O-.
7. A compound as claimed in claim 1 or 2, wherein W is absent.
8. A compound as claimed in any one of claims 1 to 7, wherein A and B are both
ethylene.
9. A compound as claimed in any one of claims 1 to 8, wherein D is CR2R3, wherein R2 is
selected from C1-5 acyl, C1-8 alkyl, and heteroaryl; and wherein C1-8 alkyl, and heteroaryl
are optionally substituted with 1 to 5 substituents selected from
C1-4 alkoxy, C1-8 alkyl, and halogen.
10. A compound as claimed in any one of claims 1 to 9, wherein R2 is selected from
C(O)CH3, C(O)CH2CH3, C(O)CH2CH2CH3, C(O)CH(CH3)2, C(O)CH2CH2CH2CH3,
CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)(CH2CH3), CH2(CH2)2CH3, and
CH2(CH2)3CH3.
11. A compound as claimed in any one of claims 1 to 9, wherein R2 is selected from
CO2CH3, CO2CH2CH3, CO2CH2CH2CH3, CO2CH(CH3)2 and CO2CH2(CH2)2CH3.
12. A compound as claimed in any one of claims 1 to 9, wherein R2 is C1-8 alkyl optionally
substituted with 1 to 5 substituents selected from C1-4 alkoxy, C1-8 alkyl, and halogen.
13. A compound as claimed in any one of claims 1 to 9, wherein R2 is selected from
CH2OCH3, CH2CH2OCH3, CH2OCH2CH3, CH2OCH2CH2CH3, CH2CH2OCH2CH3,
CH2CH2OCH2CH2CH3, CH2OCH(CH3)2, and CH2OCH2CH(CH3)2.
14. A compound as claimed in any one of claims 1 to 9, wherein R2 is a 1,2,4-oxadiazolyl
optionally substituted with C1-8 alkyl.

15. A compound as claimed in any one of claims 1 to 9, wherein R2 is 3-
methyl-l,2,4-oxadiazol-5-yl, 3-ethyl-l,2,4-oxadiazol-5-yl, 3-propyl-
l,2,4-oxadiazol-5-yl, 3-isopropyl-l,2,4-oxadiazol-5-yl, 3-butyl-l,2,4-
oxadiazol-5-yl, or 3-isobutyl-l,2,4-oxadiazol-5-yl.
16. A compound as claimed in any one of claims 1 to 8, wherein D is CR2R3, wherein R2 is
the group of Formula (C), wherein:
G is S, S(O), or S(O)2; and
Ar4 is phenyl or heteroaryl optionally substituted with 1 to 5 substituents
selected from C1-4 alkoxy, C1-8 alkyl, cyano, C1-4 haloalkoxy, C1-4 haloalkyl, C1-4
haloalkyl, and halogen.
17. A compound as claimed in any one of claims 1 to 8 and 16, wherein Ar4 is heteroaryl
optionally substituted with 1 to 5 substituents selected from C1-4 alkoxy, C1-8 alkyl,
cyano, C1-4 haloalkoxy, C1-4 haloalkyl, C1-4 haloalkyl, and halogen.
18. A compound as claimed in any one of claims 1 to 8, 16 and 17, wherein Ar4 is a
pyridyl group.
19. A compound as claimed in any one of claims 1 to 8 and 16 to 18, wherein Ar4 is 2-
pyridyl.
20. A compound as claimed in any one of claims 1 to 8 and 16 to 19, wherein G is -S-.
21. A compound as claimed in any one of claims 1 to 20, wherein R3 is H.
22. A compound as claimed in any one of claims 1 to 21, wherein R\ is H.
23. A compound as claimed in any one of claims 1 to 22, wherein Ar1 is phenyl, pyridyl,
or pyridinone optionally substituted with R9 and R10.
24. A compound as claimed in any one of claims 1 to 23, wherein R9 is selected from C1-5
acyl, vinyl, C1-8 alkyl, C1-4 alkylsulfonyl, amino, benzenesulfonyl, carboxamide,
cyclopentyl, halogen, C1-4 haloalkyl, 2,5-dioxo-imidazolidinyl, imidazolyl, pyrrolyl,
triazol-1-yl, thiadiazolyl, l,3-dioxo-l,3-dihydro-isoindolyl, pyrazolyl,
[l,3,4]oxadiazolyl, [l,2,4]oxadiazolyl, hydroxyl, oxo-cyclohexyl, phenyl, and sulfonic
acid, and wherein C1-5 acyl, C1-8 alkyl, benzenesulfonyl, and phenyl are

optionally substituted with 1 to 5 substituents selected independently from
C1-4 alkoxy, C1-8 alkyl, cyano, heteroaryl, and hydroxyl.
25. A compound as claimed in any one of claims 1 to 23, wherein R9 is selected from
acetyl, 4-hydroxy-benzenesulfonyl, 2-methoxy-ethyl, vinyl, methyl, methylsulfonyl,
ethansulfonyl, amino, 4-hydroxybenzenesulfonyl, 4-cyanophenyl, 4-methoxyphenyl,
carboxamide, cyclopentyl, fluoro, chloro, bromo, trifluoromethyl, 2,5-dioxo-
imidazolidinyl, imidazol-1-yl, pyrrolyl, triazol-1-yl, thiadiazol-4-yl, l,3-dioxo-l,3-
dihydro-isoindolyl, pyrazolyl, 5-methyl-[l,3,4]oxadiazol-2-yl, 3-methyl-
[l,2,4]oxadiazol-5-yl, hydroxyl, 4-oxo-cyclohexyl, phenyl, and sulfonic acid.
26. A compound as claimed in any one of claims 1 to 23, wherein R9 is the group of
Formula (D), wherein:
"p" and "r" are independently 0, 1, 2 or 3; and
Ri8 is H, carbo-C1-6-alkoxy, carboxy, heteroaryl or phenyl, and wherein the
heteroaryl and phenyl are optionally substituted with 1 to 5 substituents selected
independently from C1-4 alkoxy, C1-8 alkyl, halogen, C1-4 haloalkoxy, and C1-4 haloalkyl.
27. A compound as claimed in any one of claims 1 to 23, wherein R9 is 2-
methoxycarbonyl-acetyl, benzoyl, 3-oxo-butyl, 2-carboxy-ethyl, 2-carboxy-2-
oxo-ethyl, CH3(CH2)2C(O), CH3(CH2)3C(O), or CH3(CH2)4C(O).
28. A compound as claimed in any one of claims 1 to 27, wherein R10 is selected from
C1-4 alkoxy, C1-8 alkyl, amino, cyano, halogen, C1-4 haloalkoxy, C1-4 haloalkyl, and
hydroxyl.
29. A compound as claimed in any one of claims 1 to 27, wherein R10 is selected from
amino, methoxy, methyl, cyano, fluoro, chloro, bromo, trifluoromethoxy,
trifluoromethyl, and hydroxyl.
30. A compound as claimed in any one of claims 1 to 29, wherein Y is CR6.
31 A compound as claimed in claim 30, wherein R6 is H.
32. A compound as claimed in any one of claims 1 to 31, wherein U is N.

33. A compound as claimed in any one of claims 1 to 31, wherein U is CR1.
34. A compound as claimed in claim 33, wherein R1 is H.
35. A compound as claimed in claim 1 or 2, wherein:
U is N, and
X and Y are both CH.
36. A compound as claimed in claim 35, wherein:
A and B are both -CH2CH2-;
D is CR2R3, wherein R2 is selected from C(O)CH3, CO2CH2CH3,
CH2CH2CH3, and pyridin-2-ylsulfanyl; and R3 is H;
V is absent,
W is -O-;
Z is nitro; and
Ar1 is phenyl optionally substituted by R9 and R10, wherein R9 is acetyl, 2-
methoxy-ethyl, ethansulfonyl, 4-hydroxy-benzenesulfonyl, 4-cyanophenyl, 4-
methoxyphenyl, carboxamide, cyclopentyl, 2,5-dioxo-imidazolidinyl, imidazol-1-yl,
pyrrolyl, triazol-1-yl, thiadiazol-4-yl, l,3-dioxo-l,3-dihydro-isoindolyl, 4-oxo-
cyclohexyl, sulfonic acid, 2-methoxycarbonyl-acetyl, or benzoyl, 3-oxo-butyl; and R10
is amino.
37. A compound as claimed in claim 1 or 2, wherein:
U is CH,
X is CH or C-NO2, and
Y is CH.
38. A compound as claimed in claim 37, wherein:
A and B are both -CH2CH2-;
D is CR2R3, wherein R2 is selected from CO2CH2CH3, CH2CH2CH3, pyridin-
2-ylsulfanyl, CH2OCH3, and 3-methyl-l,2,4-oxadiazol-5-yl; and R3 is H;
V is absent,
W is -O-;
Z is nitro; and
Ar1 is phenyl optionally substituted by R9 and R10, wherein R9 is acetyl, vinyl,
ethansulfonyl, triazol-1-yl, 2- (3-methyl- [l,2,4]oxadiazol-5-yl)-acetyl, 5-hydroxy-l-
methyl-lH-pyrazol-3-yl, 5-trifluoromethyl-pyridin-2-yl,

46. A compound as claimed in any one of claims 1 to 43, capable of being used in the
treatment of the human or animal body by therapy.
47. A compound as claimed in any one of claims 1 to 43, capable of being used in the
prophylaxis or treatment of a metabolic disorder.
48. A pharmaceutical composition as claimed in claim 44 for prophylaxis or treatment of a
metabolic disorder.
49. A compound as claimed in any one of claims 1 to 43 capable of being used in the
manufacture of a medicament for the prophylaxis or treatment of a metabolic disorder.
50. A compound as claimed in any one of claims 1 to 43 for capable of being used in the
treatment or prophylaxis of type II diabetes, inadequate glucose tolerance, insulin
resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia,
dyslipidemia, syndrome X, or metabolic syndrome.
51. A pharmaceutical composition as claimed in claim 44 for prophylaxis or treatment of
type II diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia,
hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, syndrome X,
or metabolic syndrome.
52. A compound as claimed in any one of claims 1 to 43 capable of being used in the
manufacture of a medicament for the treatment or prophylaxis of type II diabetes,
inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia,
hypertriglyceridemia, hypercholesterolemia, dyslipidemia, syndrome X, or metabolic
syndrome.
53. A compound as claimed in any one of claims 1 to 43 capable of being used in the
treatment or prophylaxis of type II diabetes.
54. A pharmaceutical composition as claimed in claim 44 for prophylaxis or treatment of
type II diabetes.
55. A compound as claimed in any one of claims 1 to 43 capable of being used in the
manufacture of a medicament for the treatment or prophylaxis of type II diabetes.

56. A compound as claimed in any one of claims 1 to 43 capable of being used in the
controlling or decreasing weight gain in an individual.
57. A pharmaceutical composition as claimed in claim 44 for controlling or decreasing
weight gain in an individual.
58. A compound as claimed in any one of claims 1 to 43 capable of being used in the
manufacture of a medicament for controlling or decreasing weight gain in an
individual.

The present invention relates to certain certain substituted aryl and heteroaryl derivatives as shown in Formula (Ia) that are modulators of metabolism. Accordingly, compounds of the present invention are useful in the prophylaxis or treatment of metabolic disorders and complications thereof, such as, diabetes and obesity.